Accessibility / Report Error

Role of caveolin-eNOS platform and mitochondrial ATP-sensitive potassium channel in abrogated cardioprotective effect of ischemic preconditioning in postmenopausal women

Abstract

Caveolin, the protein of the caveolar membrane, interacts and binds with endothelial nitric oxide synthase (eNOS), forming a caveolin-eNOS complex leading to suppression of the eNOS activity. Caveolin, therefore, maintains eNOS in the inactivated state leading to reduced nitric oxide (NO) production. Ischemic preconditioning disrupts the caveolin-eNOS complex leading to activation of the eNOS and thus results in cardioprotection. During ischemic preconditioning, NO produces cardioprotection by the opening of the KATP channel, and the caveolin forms a suitable signalling platform facilitating the interaction of NO with the KATP channel. Estrogen deficiency has been reported to upregulate caveolin-1 expression. The article aims to review the various mechanisms that placed the women at the risk of coronary artery diseases after postmenopausal estrogen deficiency and their role in the cardioprotective effect of ischemic preconditioning.

Keywords:
Caveolin; Nitric oxide; Mito KATP; Ischemic preconditioning; Postmenopause

INTRODUCTION

Coronary artery disease (CAD) or ischemic heart disease is related to the stenosis of the coronary artery along with the arteriosclerosis. Sudden reperfusion of an ischemic heart induces a series of adverse events resulting in myocardial damage called as ischemia-reperfusion injury (I/R injury) (Collard, Gelman, 2001Collard CD and Gelman S. Pathophysiology, clinical manifestation, and prevention of ischemia-reperfusion injury. Anesthesiology . 2001;94(6):1133-8.; Kloner, 1993Kloner RA. Does reperfusion injury exist in humans? J Am Coll Cardiol . 1993;21(2):537-45.). CAD is the leading cause of mortality in industrialised countries, and the major risk factors include family history, lack of exercise, obesity, diabetes, smoking, high blood pressure, and mental stress. Treatment can be done through percutaneous transluminal coronary angioplasty, cardiac valve replacement, and bypass-grafting of coronary artery and each of them could be treated according to the extent and health of the patients (Go et al., 2013Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circulation . 2013;127(1):e6-e245.). Despite improved surgery, ischemia and reperfusion remain a major cause of myocardial injury during cardiac surgery (Liu et al., 2012Liu M, Zhang P, Chen M, Zhang W, Yu L, Yang XC et al. Aging might increase myocardial ischemia/reperfusion- induced apoptosis in humans and rats. Age (Dordr). 2012;34(3):621-32.; Marczak et al., 2012Marczak J, Nowicki R, Kulbacka J, Saczko J. Is remote ischaemic preconditioning of benefit to patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg. 2012;14(5):634-9.). Reperfusion is necessary for the recovery of ischemic myocardium from infarction. Still, it also leads to irreversible myocardial damage, and thus the protection of the myocardium from ischemia-reperfusion injury during surgery remains significant (Han et al., 2013Han S, Huang W, Liu Y, Pan S, Feng Z, Li S. Does leukocyte- depleted blood cardioplegia reduce myocardial reperfusion injury in cardiac surgery? A systematic review and meta- analysis. Perfusion. 2013;28(6):474-83.). Ischemic preconditioning (IPC) is one of the most effective ways of protecting the myocardium from ischemic attacks by various pathways (Murry, Jennings, Reimer, 1986Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation . 1986;74(5):1124-36.; Snoeckx et al., 1993Snoeckx LH, van der Vusse GJ, Coumans WA, Willemsen PH, Reneman RS. Differences in ischaemia tolerance between hypertrophied hearts of adult and aged spontaneously hypertensive rats. Cardiovasc Res . 1993;27(5):874-81.; Ferdinandy, Schulz, Baxter, 2007Ferdinandy P, Schulz R and Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/ reperfusion injury, preconditioning and postconditioning. Pharmacol Rev. 2007;59(4):418-58.; Marina Prendes et al., 2007Marina Prendes MG, González M, Savino EA, Varela A. Role of endogenous nitric oxide in classic preconditioning in rat hearts. Regul Pept. 2007;139(1-3):141-5.). However, the shielding effect of IPC has been proven to be assuaged under certain pathological conditions like hypertension, hyperlipidaemia, diabetes, aging and heart failure (Snoeckx et al., 1986Snoeckx LH, van der Vusse GJ, Coumans WA, Willemsen PH, van der Nagel T, Reneman RS. Myocardial function in normal and spontaneously hypertensive rats during reperfusion after a period of global ischemia. Cardiovasc Res .1986;20(1):67-75.; Abete et al., 1996Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, et al. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol. 1996;2(7):1777-86.; Ferdinandy, Szilvassy, Baxter, 1998Ferdinandy P, Szilvassy Z, Baxter GF. Adaptation to myocardial stress in disease states: is preconditioning a healthy heart phenomenon? Trends Pharmacol Sci. 1998;19(6):223-9.; Yadav, Singh, Sharma, 2010aYadav HN, Singh M, Sharma PL. Involvement of GSK-3β in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart. Mol Cell Biochem . 2010a;343(1-2):75-81.; 2010bYadav HN, Singh M, Sharma PL. Modulation of cardioprotective effect of ischemic preconditioning in hyperlipidaemic rat heart. Eur J Pharmacol . 2010b;643(1):78-83.; Ajmani et al., 2011Ajmani P, Yadav HN, Singh M, Sharma PL. Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart. BMC Cardiovasc Disord. 2011;11:43.). Interestingly, it has been seen that the likelihood of the incidence of CAD is higher in men than in women. Nevertheless, the incidence of CAD in women after menopause is the same as in men of the same age (Barrett-Connor, 1997Barrett-Connor E. Sex differences in coronary heart disease: Why are women so superior? the 1995 Ancel Keys Lecture. Circulation. 1997;95(1):252-64.; Clarkson et al., 1997Clarkson TB, Cline JM, Williams JK, Anthony MS. Gonadal hormone substitutes: effects on cardiovascular system. Osteoporos Int. 1997;1:S43-51.). Therefore, in this review, we are focusing on the mechanisms responsible for putting the women at the risk of CAD after postmenopausal estrogen deficiency and their involvement in the cardioprotective effect of IPC.

METHODS

Appropriate studies were collected through Pubmed, Medline, Scopus, Google Scholar online searches. The terms “ischemia-reperfusion,” “ischemia-reperfusion injury,” or “ischemic preconditioning,” along with “nitric oxide,” “mito KATP,” “caveolin,” “postmenopause,” “ovariectomized,”were used for searching. Besides, we looked for the bibliographies of relevant studies, reports, and editorial letters for writing this review.

Ischemic reperfusion injury

Myocardial ischemia occurs when the blood supply to the heart is inadequate (Gasser et al., 1994Gasser R, Schafhalter I, Wolff P, Schwarz T, Furschuss W, Klein W. Experimental models and definitions of myocardial ischemia: A review. Int J Angiol. 1994;3:154-6.). Early restoration of blood flow, i.e., reperfusion, is necessary for the survival of ischemic heart (Anaya-Prado, 2002Anaya-Prado R, Toledo-Pereyra LH, Lentsch AB, Ward PA. Ischemia/reperfusion injury. J Surg Res. 2002;105(2):248-58.). However, reperfusion after a prolonged period of ischemia itself can elicit a cascade of adverse events that paradoxically causes tissue injury that is called I/R injury (Kloner, 1993Kloner RA. Does reperfusion injury exist in humans? J Am Coll Cardiol . 1993;21(2):537-45.; Collard, Gelman, 2001Collard CD and Gelman S. Pathophysiology, clinical manifestation, and prevention of ischemia-reperfusion injury. Anesthesiology . 2001;94(6):1133-8.). Ischemia-reperfusion injury leads to myocardial stunning and microvascular injury, which leads to necrosis of myocardium (Ambrosio, Titto, 1999Ambrosio G, Tritto I. Reperfusion injury: Experimental evidence and clinical implications. Am Heart J. 1999;138(2 Pt 2):S69-75.; Yellon, Baxter, 2000Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: distant dream or near reality? Heart. 2000;83(4):381-7.).

During ischemia as indicated in Figure 1, there is reduced oxidative phosphorylation, decreased ATP level, and subsequent increase in the concentration of ADP, AMP, and phosphate (Solaini, Harris, 2005Solaini G, Harris DA. Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. Biochem J. 2005;390(Pt 2):377-394.; Powers et al., 2007Powers SK, Murlasits Z, Wu M, Kavazis AN. Ischemia-reperfusion-induced cardiac injury: A brief review. Med Sci Sports Exerc. 2007;39(9):1529-36.). The decrease in ATP activates anaerobic respiration resulting in the reduction of intracellular pH and activation of Na+/H+ antiporter (Buja, 2005Buja LM. Myocardial ischemia and reperfusion injury. Cardiovasc Pathol. 2005;14(4):170-5.). The Na+ that enters this route is normally pumped via Na+/K+ ATPase. Still, decreased ATP inhibits this efflux leading to the gradual rise in intracellular Na+ and subsequent increase in the concentration of intracellular calcium ions (Piper, Abdallah, Schäfer, 2004Piper HM, Abdallah Y, Schäfer C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res . 2004;61(3):365-71.).

FIGURE 1
Ischemic Reperfusion Injury.

AMP is converted to adenosine, which gets further converted into inosine and to hypoxanthine (Szocs, 2004Szocs K. Endothelial Dysfunction and reactive oxygen species production in ischemia/reperfusion and nitrite tolerance. Gen Physiol Biophys. 2004;23(3):265-95.). During reperfusion, hypoxanthine is oxidised by xanthine oxidase, which produces reactive oxygen species (ROS). Ischemia-reperfusion leads to the production of ROS from the mitochondria (Detmers et al., 1999Detmers PA, Lo SK, Olsen-Egbert E, Walz A, Baggiolini M, Cohn ZA. Neutrophil-activating protein-1/interleukin-8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils. J Exp Med. 1999;171(4):1155-62.; Elimadi et al., 2001Elimadi A, Sapena R, Settaf A, Le Louet H, Tillement J, Morin D. Attenuation of liver normothermic ischemia-reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative. Biochem Pharmacol . 2001;62(4):509-16.; Becker, 2004Becker LB. New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res. 2004;61(3):461-70.) which is reported to damage the cell membranes by lipid peroxidation (Halestrap, Clarke, Javadov, 2004Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion - a target for cardioprotection. Cardiovasc Res . 2004;61(3):372-85.; Halestrap, 2006Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006;34(Pt 2):232-7.; Solaini, Harris, 2005Solaini G, Harris DA. Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. Biochem J. 2005;390(Pt 2):377-394.). Moreover, in the first few minutes of reperfusion, oxidising agents such as superoxide anion, hydroxyl radical, and peroxynitrite are generated that cause marked damage to the myocardium (Bolli et al., 1989Bolli R, Jeroudi MO, Patel BS, DuBose CM, Lai EK, Roberts R, et al. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc Natl Acad Sci U S A. 1989;86(12):4695-9.). Ca++and elevated level of cytosolic ROS is known to open the mitochondrial permeability transition pore (mPTP) (Powers et al., 2007Powers SK, Murlasits Z, Wu M, Kavazis AN. Ischemia-reperfusion-induced cardiac injury: A brief review. Med Sci Sports Exerc. 2007;39(9):1529-36.; Baines, 2009Baines CP. The Mitochondrial permeability transition pore and ischemia-reperfusion injury. Basic Res Cardiol. 2009;104(2):181-8.). mPTP are multiprotein complexes that form non-selective pores in the inner mitochondrial membrane (Powers et al., 2007Powers SK, Murlasits Z, Wu M, Kavazis AN. Ischemia-reperfusion-induced cardiac injury: A brief review. Med Sci Sports Exerc. 2007;39(9):1529-36., Baines, 2009Baines CP. The Mitochondrial permeability transition pore and ischemia-reperfusion injury. Basic Res Cardiol. 2009;104(2):181-8.) and their opening leads to release of cytochrome C into the cytoplasm and initiates the process of apoptosis through caspase 9 (Cardone et al., 1998Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282(5392):1318-21.) and caspase 3 (Zou et al., 1997Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90(3):405-13.; Weiland et al., 2000Weiland U, Haendeler J, Ihling C, Albus U, Scholz W, Ruetten H, et al. Inhibition of endogenous nitric oxide synthase potentiates ischemia-reperfusion-induced myocardial apoptosis via a caspase-3 dependent pathway. Cardiovasc Res . 2000;45(3):671-8.).

The opening of mPTP causes depolarisation of the inner mitochondrial membrane resulting in a decrease in ATP production, and even stored ATP gets consumed to maintain inner mitochondrial membrane potential (Honda, Korge, Weiss, 2005Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Ann N Y Acad Sci. 2005;1047:248-58.). Depletion of ATP and elevated Ca++ during ischemic insult activate the degradative enzymes such as phospholipases (PLA2) (Ford, 2002Ford DA. Alterations in myocardial lipid metabolism during myocardial ischemia and reperfusion. Prog Lipid Res. 2002;41(1):6-26.) and calcium-activated proteases (calpains) (Chen et al., 2002Chen M, Won DJ, Krajewski S, Gottlieb RA. Calpain and mitochondria in ischemia/reperfusion injury. J Biol Chem. 2002;277(32):29181-6.) with inhibition of ATP-dependent cytosolic repair processes due to lack of ATP, eventually resulting in the loss of cellular integrity (Murphy, Steenbergen, 2008Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88(2):581-609.).

It has been reported that persistently elevated level of calcium and ROS is responsible for membrane disruption, massive cell swelling, cell lysis (Hausenloy, Yellon, 2004Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia- reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res . 2004;61(3):448-60.) and ultimately contribute to necrotic cell death (Zong, Thompson, 2006Zong WX, Thompson CB.Necrotic death as a cell fate. Genes Dev. 2006;20(1):1-15.). Necrosis results in rapid loss of plasma membrane integrity due to increased oxidative stress, cytosolic calcium level, and decreased level of ATP (Ermak, Davies, 2002Ermak G, Davies KJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol. 2002;38(10):713-21.; Bartosz, 2009Bartosz G. Reactive oxygen species: destroyers or messengers? BiochemPharmacol. 2009;77(8):1303-15).

Moreover, I/R injury has been well demonstrated to cause organ damage in the brain, heart, lungs, liver, kidneys, and skeletal muscle (Novgorodov, Gudz, 2009Novgorodov SA, Gudz TI. Ceramide and mitochondria in ischemia/reperfusion. J Cardiovasc Pharmacol . 2009;53(3):198-208.). Several therapeutic strategies such as controlled reperfusion, preconditioning, postconditioning, and several pharmacological interventions, for example, adenosine (Lozza et al., 1997Lozza G, Conti A, Ongini E, Monopoli A. Cardioprotective effects of adenosine A1and A2A receptor agonists in the isolated rat heart. Pharmacol Res. 1997;35(1):57-64.; Moukarbel, Ayoub, Abchee, 2004Moukarbel GV, Ayoub CM, Abchee AB. Pharmacological therapy for myocardial reperfusion injury. Curr Opin Pharmacol. 2004;4(2):147-53.), renin-angiotensin system antagonist (Paz et al., 1998Paz Y, Gurevitch J, Frolkis I, Matsa M, Kramer A, Locker C, et al. Effects of an angiotensin II antagonist on ischemic and nonischemic isolated rat hearts. Ann Thorac Surg . 1998;65(2):474-9.), calcium antagonists (Segawa et al., 2000Segawa D, Sjöquist PO, Wang QD, Gonon A, Nordlander M, Rydén L. Calcium antagonist protects the myocardium from reperfusion injury by interfering with mechanisms directly related to reperfusion: an experimental study with the ultrashort-acting calcium antagonist clevidipine. J Cardiovasc Pharmacol . 2000;36(3):338-43.), antioxidants (Marczin et al., 2003Marczin N, El-Habashi N, Hoare GS, Bundy RE, Yacoub M. Antioxidants in myocardial ischemia-reperfusion injury: therapeutic potential and basic mechanisms. Arch Biochem Biophys. 2003;420(2):222-36.), sodium-hydrogen exchange inhibitors (Hennan et al., 2006Hennan JK, Driscoll EM, Barrett TD, Fischbach PS, Lucchesi BR. Effect of sodium/hydrogen exchange inhibition on myocardial infarct size after coronary artery thrombosis and thrombolysis. Pharmacology. 2006;78(1):27-37.), iron chelators (Tang et al., 2008Tang WH, Wu S, Wong TM, Chung SK, Chung SS. Polyol pathway mediates iron-induced oxidative injury in ischemic- reperfused rat heart. Free Radic Biol Med. 2008;45(5):602-10.), N-methylated synthetic sphingolipid analog (Gundewar, Lefer, 2008Gundewar S, Lefer DJ. Sphingolipid therapy in myocardial ischemia reperfusion injury. Biochim Biophys Acta. 2008;1780(3).571-6.), flavonoids (Yadav et al., 2015Yadav HN, Varshney V, Singh NK, Sharma PL. Quercetin: a phytoestrogen attenuate GSK-3b inhibitors induced delayed cardioprotection in diabetic rat heart. Pharmacologia. 2015;6:293-9.) and exenatide (Timmers et al., 2009Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol . 2009;53(6):501-10.) have shown to reduce ischemia-reperfusion-induced myocardial injury.

Concept of preconditioning

In 1986, Murry and co-workers provided the strategy to prevent I/R injury. They found that short transient periods of sublethal ischemia accompanied by reperfusion protect the myocardial tissue from prolonged ischemic insult, which is known as “Ischemic preconditioning” (IPC) (Murry, Jennings, Reimer, 1986Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation . 1986;74(5):1124-36.; Tomai et al., 1999Tomai F, Crea F, Chiariello L, Gioffrè PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation . 1999;100(5):559-63.). This potent cardioprotective strategy has been observed in all animal species examined to date, including mammals (Cohen, Liu, Downey, 1991Cohen MV, Liu GS, Downey JM. Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits. Circulation . 1991;84(1):341-9.). Ischemic preconditioning is a biphasic process, an early phase that begins within minutes and slowly decreases within 2-3 hours and called classical preconditioning (Downey, Cohen, 1997Downey M, Cohen MV. Preconditioning: What it is and how it works. Dialogues in Cardiovascular Medicine. 1997;2:179-96.; Yellon, Downey, 2003Yellon DM, Downey JM. Preconditioning the myocardium from cellular physiology to clinical cardiology. Physiol Rev .2003;83(4):1113-5.). The other is a late phase that occurs after 12-24 hours of ischemic insult and lasts 3-4 days and called as late phase preconditioning or second window of protection (Kuzuya et al., 1993Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, et al. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res . 1993;72(6):1293-9.; Marber et al., 1993Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation . 1993;88(3):1264-72.). The early phase IPC only protects from myocardial infarction, but the late phase IPC also protects from myocardial stunning (Bolli, 1996Bolli R. The early and late phases of preconditioning against myocardial stunning and the essential role of oxyradicals in the late phase: an overview. Basic Res Cardiol . 1996;91(1):57-63.; Sisakiyan, 2008Sisakiyan H. Pathophysiology, clinical significance and possibilities of cardioprotection in myocardial stunning, hibernation and preconditioning. New Am Med J. 2008;2:28-34.).

Many pharmacological agents have been shown a preconditioning-like effect, i.e., adenosine (Liu et al., 1991Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation . 1991;84(1):350-6.; Yao, Gross, 1994Yao Z, Gross GJ. A Comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs. Efficacy, time course, and role of KATP channels. Circulation . 1994;89(3):1229-36.), bradykinin (Goto et al., 1995Goto M, Liu Y, Yang XM, Ardell JL, Cohen MV, Downey JM. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res . 1995;77(3):611-21.; Yoshida et al., 2005Yoshida H, Kusama Y, Kodani E, Yasutake M, Takano H, Atarashi H et al. Pharmacological preconditioning with bradykinin affords myocardial protection through NO-dependent mechanisms. Int Heart J. 2005;46(5):877-87.), protein kinase C activators (Ytrehus, Liu, Downey, 1994Ytrehus K, Liu Y, Downey JM. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol . 1994;266(3 Pt 2):H1145-52.), ATP sensitive potassium channel openers (Parratt, Kane, 1994Parratt JR, Kane KA. KATP channels in ischaemic preconditioning. Cardiovasc Res . 1994;28(6):783-7.; Schulz, Rose, Heusch, 1994Schulz R, Rose J, Heusch G. Involvement of activation of ATP-dependent potassium channels in ischemic preconditioning in swine. Am J Physiol . 1994;267(4 Pt 2):H1341-52.), opioids (Schultz et al., 1995Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol . 1995;268(5 Pt 2):H2157-61.), norepinephrine (Thornton et al., 1993Thornton JD, Daly JF, Cohen MV, Yang XM, Downey JM Catecholamines can induce adenosine receptor-mediated protection of the myocardium but do not participate in ischemic preconditioning in the rabbit. Circ Res . 1993;73(4):649-55.), acetylcholine (Yao, Gross, 1993Yao Z, Gross GJ. Role of nitric oxide, muscarinic receptors, and the ATP-sensitive K+ channel in mediating the effects of acetylcholine to mimic preconditioning in dogs. Circ Res . 1993;73(6):1193-201.), α1 adrenergic receptors agonists (Banerjee et al., 1993Banerjee A, Locke-Winter C, Rogers KB, Mitchell MB, Brew EC, Cairns CB, et al. Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res . 1993;73(4):656-70.), estrogen (Lee et al., 2002Lee TM, Su SF, Chou TF, Tsai CH. Pharmacologic preconditioning of estrogen by activation of the myocardial adenosine triphosphate-sensitive potassium channel in patients undergoing coronary angioplasty. J Am Coll Cardiol . 2002;39(5):871-7.), nitroglycerin (Du et al., 2004Du YH, Peng J, Huang ZZ, Jiang DJ, Deng HW, Li YJ. Delayed cardioprotection afforded by nitroglycerin is mediated by alpha-CGRP via activation of inducible nitric oxide synthase. Int J Cardiol. 2004;93(1):49-54.), sildenafil (Kukreja et al., 2005Kukreja RC, Salloum F, Das A, Ockaili R, Yin C, Bremer YA, et al. Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications. VasculPharmacol. 2005;42(5-6):219-32.), ang (1-7) (Pachauri et al., 2017Pachauri P, Garabadu D, Goyal A, Upadhyay PK. Angiotensin (1-7) facilitates cardioprotection of ischemic preconditioning on ischemia-reperfusion-challenged rat heart. Mol Cell Biochem . 2017;430(1-2):99-113.) atrial natriuretic peptide (ANP) (Charan et al., 2016Charan K, Goyal A, Gupta JK, Yadav HN. Role of atrial natriuretic peptide in ischemic preconditioning-induced cardioprotection in the diabetic rat heart. J Surg Res . 2016;201(2):272-8.) and heme oxygenase activator (Gupta et al., 2017Gupta I, Goyal A, Singh NK, Yadav HN, Sharma PL. Hemin, a heme oxygenase-1 inducer, restores the attenuated cardioprotective effect of ischemic preconditioning in isolated diabetic rat heart. Hum Exp Toxicol . 2017;36(8):867-75.) which is called as pharmacological preconditioning.

Moreover, a brief episode of ischemia followed by reperfusion to other organs produces protection against I/R injury on the heart, and it is known as remote preconditioning (RPC) (Przyklenk et al., 1993Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P.Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation . 1993;87(3):893-9.). Remote preconditioning has also been reported to occur in human beings (Kloner, Jennings, 2001Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation . 2001;104(24):2981-9.; Walsh et al., 2007Walsh SR, Tang T, Sadat U, Dutka DP, Gaunt ME. Cardioprotection by remote ischemic preconditioning. Br J Anaesth. 2007;99(5):611-6.). Further, brief occlusion of the anterior mesenteric artery protects the heart against infarction is known as mesenteric preconditioning (Gho et al., 1996Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation . 1996;94(9):2193-00.; Santos et al., 2008Santos CH, Gomes OM, Pontes JC, Miiji LN, Bispo MA. The ischemic preconditioning and postconditioning effect on the intestinal mucosa of rats undergoing mesenteric ischemia/ reperfusion procedure. Acta Cir Bras. 2008;23(1):22-8.). The brief occlusion of the renal artery offers heart defense against infarction and known as renal preconditioning (Diwan et al., 2008Diwan V, Kant R, Jaggi AS, Singh N, Singh D. Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem. 2008;315(1-2):195-201.). Similarly, brief episodes of aortic occlusion protect against infarction to the heart is known as remote aortic preconditioning (Khanna et al., 2008Khanna G, Diwan V, Singh M, Singh N, Jaggi AS. Reduction of ischemic, pharmacological and remote preconditioning effects by an antioxidant N-acetyl cysteine pretreatment in isolated rat heart.YakugakuZasshi. 2008;128(3):469-77.).

Brief episodes of occlusion and reperfusion of the left circumflex artery salvage the myocardium region from subsequent prolonged ischemia provided by the left anterior descending coronary artery. Paradoxically, the transfer of coronary effluent from the preconditioned heart to non-preconditioned heart limits infarct size in the latter against I/R injury, which is called as intracardiac preconditioning (Przyklenk et al., 2003Przyklenk K, Darling CE, Dickson EW, Whittaker P. Cardioprotection ‘outside the box’the evolving paradigm of remote preconditioning. Basic Res Cardiol . 2003;98(3):149-57.; Galagudza et al., 2008Galagudza MM, Blokhin IO, Shmonin AA, Mischenko KA. Reduction of Myocardial ischemia-reperfusion injury with pre-and postconditioning: molecular mechanism and therapeutic targets. Cardiovasc Hematol Disord Drug Targets. 2008;8(1):47-65.).

Molecular mechanism of the cardioprotective effect of preconditioning

Preconditioning results in the generation of various endogenous ligands, i.e., adenosine (Liu et al., 1991Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation . 1991;84(1):350-6.), bradykinin (Goto et al., 1995Goto M, Liu Y, Yang XM, Ardell JL, Cohen MV, Downey JM. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res . 1995;77(3):611-21.; Cohen et al., 2007Cohen MV, Philipp S, Krieg T, Cui L, Kuno A, Solodushko V, et al. Preconditioning-mimetics Bradykinin and DADLE Activate PI3-Kinase Through Divergent Pathways. J Mol Cell Cardiol . 2007;42(4):842-51.), opioids (Schultz et al., 1995Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol . 1995;268(5 Pt 2):H2157-61.) and norepinephrine (Banerjee et al., 1993Banerjee A, Locke-Winter C, Rogers KB, Mitchell MB, Brew EC, Cairns CB, et al. Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res . 1993;73(4):656-70.), acetylcholine (Yao, Gross, 1993Yao Z, Gross GJ. Role of nitric oxide, muscarinic receptors, and the ATP-sensitive K+ channel in mediating the effects of acetylcholine to mimic preconditioning in dogs. Circ Res . 1993;73(6):1193-201.) as indicated in Figure 2.

FIGURE 2
Molecular Mechanism of Early Ischemic Preconditioning.

They bind to their respective G-protein coupled receptors and initiates a cascade of signal transduction, which leads to activation of PI3K (Mocanu et al., 2002Mocanu MM, Bell RM, Yellon DM. PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning. J Mol Cell Cardiol . 2002;34(6):661-8.) and phospholipase C (Tyagi, Tayal, 2002Tyagi P, Tayal G. Ischemic preconditioning of the myocardium. Acta Pharmacol Sin. 2002;23(2):865-70.). Activated

PI3K generates phosphatidyl-inositol 3,4,5-triphosphate (PIP3) from cell membrane lipid phosphatidylinositol 3,4-bisphosphate (PIP2) leading to activation of the phosphoinositide-dependent kinase (PDK1) and subsequent activation of protein kinase B (Akt) and p70S6-kinase (Jonassen, Mjos, Sack, 2004Jonassen AK, Mjøs OD, Sack MN. p70S6 Kinase is a functional target of insulin activated Akt cell-survival signalling. Biochem Biophys Res Commun. 2004;315(1):160-5.; Kis, Yellon, Baxter, 2003Kis A, Yellon DM, Baxter GF. Second window of protection following myocardial preconditioning: an essential role for PI3 kinase and p70S6 kinase. J Mol Cell Cardiol . 2003;35(9):1063-71.). PI3K activation reported to upstream of PKC (Tong et al., 2000Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res . 2000;87(4):309-15.), GSK3β (Tong et al., 2002Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. Circ Res . 2002;90(4):377-9.), and activation of mitochondrial ATP-sensitive K channels (mito KATP) (Oldenburg et al., 2002Oldenburg O, Qin Q, Sharma AR, Cohen MV, Downey JM, Benoit JN. Acetylcholine leads to free radical production dependent on K(ATP) channels, G(i) proteins, phosphatidylinositol 3-kinase and tyrosine kinase. Cardiovasc Res . 2002;55(3):544-52.; Garlid et al., 1997Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D’Alonzo AJ, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res . 1997;81(6):1072-82.). The activated phospholipase C leads to the generation of two-second messengers, diacylglycerol (DAG) and inositol triphosphate (IP3), by hydrolysis of PIP2. The DAG activates protein kinase C by translocating it from cytosol to perinuclear membrane (Mitchell et al., 1995Mitchell MB, Meng X, Ao L, Brown JM, Harken AH, Banerjee A. Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res . 1995:76(1):73-81.; Tong et al., 2004Tong H, Rockman HA, Koch WJ, Steenbergen C, Murphy E. G protein coupled receptor internalization signaling is required for cardioprotection in ischemic preconditioning. Circ Res . 2004;94(8):1133-41.). ROS generation during preconditioning also activates PKC (Penna et al., 2009Penna C, Mancardi D, Rastaldo R, Pagliaro P. Cardioprotection: a radical view Free radicals in pre and postconditioning. Biochim Biophys Acta . 2009;1787(7):781-93.; Baines, Goto, Downey, 1997Baines CP, Goto M, Downey JM. Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J Mol Cell Cardiol. 1997;29(1):207-16.). PKC activation is important in the opening of mito KATP (Sato, O’Rourke, Marban, 1998Sato T, O’Rourke B, Marbán E. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res . 1998;83(1):110-14.; Murphy, 2004Murphy E. Primary and secondary signaling pathways in early preconditioning that converge on the mitochondria to produce cardioprotection. Circ Res . 2004;94(1):7-16.). PKCε, as well as PKCδ, has been demonstrated to mimic preconditioning due to the opening of mito KATP (Dreixler et al., 2008Dreixler JC, Shaikh AR, Shenoy SK, Shen Y, Roth S. Protein kinase C subtypes and retinal ischemic preconditioning. Exp Eye Res.2008;87(4):300-11.).

The opening of mito KATP channels can protect the mitochondria from Ca2+overload and prevent cytochrome c loss (Garlid et al., 1997Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D’Alonzo AJ, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res . 1997;81(6):1072-82.; Korge, Honda, Weiss, 2002Korge P, Honda HM, Weiss JN.Protection of cardiac mitochondria by diazoxide and protein kinase C: implications for ischemic preconditioning. Proc Natl Acad Sci U S A . 2002;99(5):3312-7.). As potassium enters the mitochondria, it causes them to release free radicals, i.e., ROS (Downey, Cohen, 2006Downey JM, Cohen MV.Reducing infarct size in the setting of acute myocardial infarction. Prog Cardiovasc Dis. 2006;48(5):363-71.). Although a massive burst of ROS leads to cell damage, a moderate release of ROS during nonlethal short episodes of ischemia play a significant triggering role in the signal transduction pathways of IPC (Vanden et al., 1998Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT.Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem . 1998;273(29):18092-8.). PKCε also forms a complex with mitochondrial permeability transition pore (mPTP) (Baines et al., 2003Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, et al. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003;92(8):873-80.; Zoratti et al., 2009Zoratti M, De Marchi U, Gulbins E, Szabo I. Novel channels of the inner mitochondrial membrane. Biochim Biophys Acta . 2009;1787(5):351-63.), which leads to decrease in the release of cytochrome C and apoptotic cell death (Kroemer, Dallaporta, Resche-Rigon, 1998Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol. 1998;60:619-42.; Hausenloy, Yellon, 2004Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia- reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res . 2004;61(3):448-60.).

Clinical aspects of ischemic preconditioning

Numerous studies have been well demonstrated the clinical potential of preconditioning in patients of ischemic heart disease. Various in vivo models of ischemic preconditioning in human myocardium have been shown including warm-up phenomenon, preinfarction angina, angioplasty studies, and other surgical studies (Yellon, Downey, 2003Yellon DM, Downey JM. Preconditioning the myocardium from cellular physiology to clinical cardiology. Physiol Rev .2003;83(4):1113-5.). The ischemic preconditioning phenomenon was well demonstrated in the human atrial muscle of patients undergoing coronary artery bypass graft surgery (CABG) (Walker et al., 1994Walker DM, Marber MS, Walker JM, Yellon DM. Preconditioning in isolated superfused rabbit papillary muscles. Am J Physiol . 1994;266(4 Pt 2):H1534-40.). Other invitro studies also indicated that the δ-opioid receptor as a trigger in human myocardium subjected to ischemic preconditioning (Bell et al., 2000Bell SP, Sack MN, Patel A, Opie LH, Yellon DM. Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle. J Am Coll Cardiol. 2000;36(7):2296-302.). Myocardial biopsies were taken after 10min of cross-clamping exhibited significantly higher content of ATP and reduced release of troponin (Tomai et al., 1999Tomai F, Crea F, Chiariello L, Gioffrè PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation . 1999;100(5):559-63.; Ylitalo, Peuhkurinen, 2000Ylitalo K, Peuhkurinen K. Adaptation to myocardial ischemia during repeated ventricular pacing in patients with coronary artery disease. Scand Cardiovasc J. 2000;34(2):134-41.). Pharmacological recruitment of protection using adenosine (Mentzer et al., 1997Mentzer RM, Rahko PS, Molina-Viamonte V, Canver CC, Chopra PS, Love RB, et al. Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery. Am J Cardiol. 1997;79(12A):38-43.), volatile anesthetics, i.e., isoflurane (Belhomme et al., 1999Belhomme D, Peynet J, Louzy M, Launay JM, Kitakaze M, Menasche, P. Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery. Circulation . 1999;100:II340-4.; Riess, Stowe, Wartlier, 2004Riess ML, Stowe DF, Warltier DC. Cardiac pharmacological preconditioning with volatile anesthetics: from bench to bedside? Am J Physiol Heart Circ Physiol . 2004;286(5):H1603-7.; Frassdorf et al., 2009Frassdorf J, Borowski A, Ebel D, Feindt P, Hermes M, Meemann Tet al. Impact of preconditioning protocol on anesthetic-induced cardioprotection in patients having coronary artery bypass surgery. J Thorac Cardiovasc Surg.2009;137(6):1436-42.) is another interesting alternative to provide preconditioning mediated cardioprotection in patients undergoing CABG (Tomai et al., 1999Tomai F, Crea F, Chiariello L, Gioffrè PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation . 1999;100(5):559-63., Ylitalo, Peuhkurinen, 2000Ylitalo K, Peuhkurinen K. Adaptation to myocardial ischemia during repeated ventricular pacing in patients with coronary artery disease. Scand Cardiovasc J. 2000;34(2):134-41.).

The Post-transluminal coronary angioplasty (PTCA) procedure involves repeated intracoronary balloon inflations with intervening periods of perfusion which was characterized by less anginal pain, less ST-segment shift, and lower mean pulmonary artery pressure, despite a reduction in cardiac vein flow and unchanged coronary wedge pressure during second balloon inflation (Yellon, Downey, 2003Yellon DM, Downey JM. Preconditioning the myocardium from cellular physiology to clinical cardiology. Physiol Rev .2003;83(4):1113-5.). Pre-treatment with Nicorandil, a mito KATP channel opener preconditions the myocardium by preventing the incidence of ventricular arrhythmias and myocardial dysfunction after coronary reperfusion (Kato et al., 2001Kato T, Kamiyama T, Maruyama Y, Tanaka S, Yoshimoto N. Nicorandil, a potent cardioprotective agent, reduces qt dispersion during coronary angioplasty. Am Heart J . 2001;141(6):940-3.).

Further, adenosine preconditioning decreases the severity of ischemia during the first balloon inflation, and that was significantly improved on subsequent balloon inflations during PTCA (Leesaret al., 2003Leesar MA, Stoddard MF, Xuan YT, Tang XL, Bolli, R. Nonelectrocardiographic evidence that ischemic preconditioning and adenosine preconditioning exist in humans. J Am Coll Cardiol . 2003;42(3):437-45.). The warm-up phenomenon improves coronary blood flow and reduced myocardium oxygen consumption during the second period of exertion (Okazaki et al., 1993Okazaki Y, Kodama K, Sato H, Kitakaze M, Hirayama A, Mishima M et al. Attenuation of increased regional myocardial oxygen consumption during exercise as a major cause of warm-up phenomenon. J Am Coll Cardiol . 1993;21(7):1597-1604.; Marber, Joy, Yellon, 1994Marber MS, Joy MD, Yellon DM. Is warm-up angina ischemic preconditioning. Br Heart J . 1994;72(3):213-5.). This endogenous adaptation has been studied during successive ergometer or walking tests and during repeated atrial and ventricular pacings (Joy, Cairns, Springings, 1987Joy M, Cairns AW, Sprigings D. Observations on the warm-up phenomenon in angina pectoris. Br Heart J. 1987;58(2):116-21.; Ylitalo, Peuhkurinen, 2000Ylitalo K, Peuhkurinen K. Adaptation to myocardial ischemia during repeated ventricular pacing in patients with coronary artery disease. Scand Cardiovasc J. 2000;34(2):134-41.; Ylitalo et al., 2001Ylitalo K, Niemela M, Linnaluoto M, Valkama J, Mattila K, Peuhkurinen K. Evidence suggesting coronary vasodilatation as the principal mechanism in the warm-up phenomenon. Am Heart J . 2001;141:5A-12A.). Patients with pre-infarct angina were found to have smaller creatine kinase output, less arrhythmias, less stunning and heart failure and better in-hospital outcome after thrombolytic therapy than patients without pre-infarction angina (Anzai et al., 1995Anzai T, Yoshikawa T, Asakura Y, Abe S, Akaishi M, Mitamura Het al. Preinfarction angina as a major predictor of left ventricular function and long-term prognosis after first Q wave myocardial infarction. J Am Coll Cardiol . 1995;26(2):319-27.; Andreotti et al., 1996Andreotti F, Pasceri V, Hackett DR, Davies GJ, Haider AW, Maseri A. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med. 1996;334(1):7-12.; Kloner et al., 1998Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K, Yoo K, et al. Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B. Circulation . 1998;97(11):1042-5.; Skyschallyet al., 2005Skyschally A, Gres P, Heusch P, Martin C, Haude M, Erbel R, et al. Preinfarction angina: no interference of coronary microembolization with acute ischemic preconditioning. J Mol Cell Cardiol . 2005;39(2):355-61.; Yan et al., 2009Yan H, Song L, Yang J, Sun Y, Hu D. The association between pre-infarction angina and care-seeking behaviors and its effects on early reperfusion rates for acute myocardial infarction. Int J Cardiol . 2009;135(1):86-92.). Pre-infarct angina may activate endogenous antithrombotic or fibrinolytic mechanisms, which gives more time for revascularization procedures (Haider et al., 1995Haider AW, Andreotti F, Hackett DR, Tousoulis D, Kluft C, Maseri A, et al. Early spontaneous intermittent myocardial reperfusion during acute myocardial infarction is associated with augmented thrombogenic activity and less myocardial damage. J Am Coll Cardiol . 1995;26(3):662-7.; Tomoda, Aoki, 1999Tomoda H, Aoki N. Comparison of protective effects of preinfarction angina pectoris in acute myocardial infarction treated by thrombolysis versus primary coronary angioplasty with stenting. Am J Cardiol . 1999;84(6):621-5.).

The findings from many preclinical studies in which cardioprotection has been seen in healthy animal hearts might not be reproducible in the human myocardium due to several factors such as old age, the presence of comorbid disease such as diabetes, hypertension, hypercholesterolemia (Goyal, Agrawal, 2017Goyal A, Agrawal N. Ischemicpreconditioning:Interruptionof various disorders. J Saudi Heart Assoc. 2017;29(2):116-27.; Varshney et al., 2017Varshney V, Goyal A, Gupta JK, Yadav HN. Role of erythropoietin in ischemic postconditioning induced cardioprotection in hyperlipidemic rat heart. J Indian College Cardiol. 2017;7:72-7.). Moreover, the timing and duration of myocardial ischemia, use of pharmacological agents such as oral sulfonylurea drugs or cyclooxygenase 2 inhibitors and practical constraints may complicate preconditioning protocol and limit the benefits of these drugs under such clinical conditions (Schulman, Latchman, Yellon, 2001Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol . 2001:281(4);H1630-6.; Riess, Stowe, Wartlier, 2004Riess ML, Stowe DF, Warltier DC. Cardiac pharmacological preconditioning with volatile anesthetics: from bench to bedside? Am J Physiol Heart Circ Physiol . 2004;286(5):H1603-7.).

Role of nitric oxide (NO) in preconditioning

It has been demonstrated that NO is involved in preconditioning induced PKC translocation (Ping et al., 1999Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res . 1999;84(5):587-604.). Because inhibition of PI3K leads to the reduction in the generation of NO, it can be concluded that PI3K activates PKC via eNOS mediated mechanism (Tong et al., 2000Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res . 2000;87(4):309-15.). Akt also directly activates eNOS (Fulton et al., 1999Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature . 1999;399(6736):597-601.; Dimmeler et al., 1999Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601-5.), and NO generated by eNOS is proposed to initiate preconditioning (Ping et al., 1999Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res . 1999;84(5):587-604.). It has been demonstrated that NO generated during preconditioning is a trigger for late PC (Ping et al., 1999Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res . 1999;84(5):587-604.), but the role of NO in early PC is controversial (Woolfson et al., 1995Woolfson RG, Patel VC, Neild GH, Yellon DM. Inhibition of nitric oxide synthesis reduces infarct size by an adenosine-dependent mechanism. Circulation . 1995;91(5):1545-51.). The mechanism by which NO activates PKC is still to be elucidated. Because the antioxidant mercaptopropionyl glycine blocks NO-donor induced late PC (Takano et al., 1998Takano H, Tang XL, Qiu Y, Guo Y, French BA, Bolli R. Nitric Oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ Res . 1998;83(1):73-84.), it can be postulated that NO-derived reactive species (ONOO-) may activate PKC either by direct oxidative modification or via activation of phospholipases (Ping et al., 1999Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res . 1999;84(5):587-604.). eNOS generates NO, which results in activation of guanylyl cyclase, which via protein kinase G is reported to activate a mitochondrial PKC, which results in the opening of the mito KATP channel (Costa et al., 2005Costa AD, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, et al. Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res . 2005;97(4):329-36.).

Biology of caveolae

The term Caveolae was coined by Yamada in 1955Yamada E. The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol. 1955;1(5):445-58. to reflect their appearance as “little caves”, which is 50-100 nm in diameter (Roth, Porter, 1964Roth TF, Porter KR. Yolk Protein Uptake in the oocyte of the mosquito aedes aegyti. J Cell Biol. 1964;20(2):313-32.). Caveolae are plasma membrane invaginations on the surface of endothelial cells (Palade, 1953Palade GE. Fine structure of blood capillaries. J Appl Phys. 1953, 24:1424-36.). Glenney in 1989Glenney JR Jr. Tyrosine Phosphorylation of a 22-kDa Protein is correlated with transformation by Rous sarcoma virus. J Biol Chem . 1989;264(34):20163-6. first identified caveolin as a 21-22KDa tyrosine-phosphorylated substrate in chick fibroblasts. Caveolae are the specialized membrane domains, triton insoluble, cholesterol and sphingolipids enriched protein (Garcia-Cardena et al., 1997García-Cardeña G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem . 1997;272(41):25437-40.) which form lipid raft with caveolins (Williams, Lisanti, 2004Williams TM, Lisanti MP. The caveolin genes: from cell biology to medicine. Ann Med. 2004;36(8):584-95.) that serves as organizing centers for cellular signal transduction (Shaul, Anderson, 1998Shaul PW, Anderson RG. Role of plasmalemmal caveolae in signal transduction. Am J Physiol . 1998;275(5):L843-51.; Patel, Murray, Insel, 2008Patel HH, Murray F, Insel PA. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol. 2008;48:359-91.). Caveolin also possesses a scaffolding domain that facilitates the interaction and organization of signaling molecules to provide coordinated and efficient signal transduction (Okamoto et al., 1998Okamoto T, Schlegel A, Scherer PE, Lisanti MP. Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signalling Complexes” at the Plasma Membrane. J Biol Chem . 1998;273(10):5419-22.).

The caveolin gene family consists of three members that differ in their pattern of expression in different cell types. Caveolin-1 (cav-1) and caveolin-2 (cav-2) are co-expressed in many cell types including adipocytes, endothelial cells, epithelial cells and fibroblast (Scherer et al., 1994Scherer PE, Lisanti MP, Baldini G, Sargiacomo M, Mastick CC, Lodish HF. Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles. J Cell Biol . 1994;127(5):1233-43.; Scherer et al., 1997Scherer PE, Lewis RY, Volonte D, Engelman JA, Galbiati F, Couet J, et al. Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo. J Biol Chem . 1997;272(46):29337-46.) whereas Caveolin-3 (cav-3) is restricted to the skeleton and smooth muscles including cardiac myocytes (Scherer et al., 1994Scherer PE, Lisanti MP, Baldini G, Sargiacomo M, Mastick CC, Lodish HF. Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles. J Cell Biol . 1994;127(5):1233-43.; Song et al., 1996Song KS, Li Shengwen, Okamoto T, Quilliam LA, Sargiacomo M, Lisanti MP. Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J Biol Chem . 1996;271(16):9690-7.; Minetti et al., 1998Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, et al. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet. 1998;18(4):365-8.; Galbiati et al., 2001Galbiati F, Engelman JA, Volonte D, Zhang XL, Minetti C, Li M, et al. Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex and t-tubule abnormalities. J Biol Chem . 2001;276(24):21425-33.). It is also found in a variety of other cells, including the immune and nervous system. Cav-1 is a specific marker of caveolae and is up-regulated by oxidized LDL, estrogen deficiency, and hyperglycemia (Sharma, Singh, Sharma, 2011Sharma S, Singh M, Sharma PL. Beneficial effect of insulin in hyperhomocysteinemia and diabetes mellitus induced vascular endothelium dysfunction: role of phosphoinositide dependent kinase and protein kinase B. Mol Cell Biochem . 2011;348:21-32.). It serves as a cholesterol-binding protein and helps cholesterol to move from endoplasmic reticulum through the golgi apparatus to the plasma membrane of endothelial cells (Fulton, Gratton, Sessa, 2001Fulton D, Gratton JP, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn’t calcium/calmodulin enough? J Pharmacol Exp Ther . 2001;299(3):818-24.). Caveolin is a negative regulator of eNOS as its interaction, and binding suppresses the activity of eNOS by making a caveolin-eNOS complex (Minshall et al., 2002Minshall RD, Tiruppathi C, Vogel SM, Malik AB. Vesicle formation and traffickng in endothelial cells and regulation of endothelial barrier function. Histochem Cell Biol. 2002;117(2):105-12.; Feron, Balligand, 2006Feron O, Balligand JL. Caveolin and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res . 2006;69(4):788-97.; Koneru et al., 2007Koneru S, Penumathsa SV, Thirunavukkarasu M, Samuel SM, Zhan L, Han Z, et al. Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. Am J Physiol Heart Circ Physiol . 2007;292(5):H2060-72.). Alterations in caveolin/eNOS interaction influence various mechanisms of diseases such as atherosclerosis, diabetes, cirrhosis (Spieker, Lüscher, Noll, 2001Spieker LE, Lüscher TF, Noll G. Current Strategies and perspectives for correcting endothelial dysfunction in atherosclerosis. J Cardiovasc Pharmacol . 2001;38:S35-41.; Elçioglu et al., 2010Elçioglu KH, Kabasakal L, Cetinel S, Conturk G, Sezen SF, Ayanoğlu-Dülger G. Changes in caveolin -1 expression and vasoreactivity in the aorta and corpus cavernosum of fructose and streptozotocin-induced diabetic rats. Eur J Pharmacol. 2010;642(1-3):113-20.; Xu et al., 2008Xu B, Zhu GH, Weng JF, Cai WS, Xia JT, Li SH. The roles of caveolin-1and endothelial nitric oxide synthase in the development of portal hypertension in rats with liver cirrhosis. Zhonghua Gan Zang Bing Za Zhi. 2008;16(3):184-7.; Ajmani et al., 2011Ajmani P, Yadav HN, Singh M, Sharma PL. Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart. BMC Cardiovasc Disord. 2011;11:43.).

Various signaling molecules have been shown to localize within caveolae. These include SCR family, tyrosine kinase, GPCR, members of Ras-MAPK cascade, and nitric oxide synthase (Ostrom, Insel, 2004Ostrom RS, Insel PA. The Evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology. Br J Pharmacol . 2004;143(2):235-45.; Insel et al., 2005Insel PA, Head BP, Patel HH, Roth DM, Bundey RA, Swaney JS. Compartmentation of G-protein coupled receptors and their signalling components in lipid rafts and caveolae. Biochem Soc Trans . 2005;33(Pt 5):1131-4.). It has been documented that phosphatidylinositol-3 kinase/protein kinase B (PI-3K/AKT) pathway, PKC and PKA in caveolae interact with caveolin and modulate the opening of ATP-dependent K+ channels and regulate the survival of cell facilitating the interaction of NO with KATP channel by forming a suitable signaling platform (Razani, Lisanti, 2001Razani B, Lisanti MP. Two distinct caveolin-1 domains mediate the functional interaction of caveolin-1 with protein kinase A. Am J Physiol Cell Physiol. 2001;281(4):C1241-50.). Caveolins (cav-1 and cav-3) maintains eNOS in the inactivated state, which leads to a decrease in NO production (Quinlan et al., 2008Quinlan CL, Costa AD, Costa CL, Pierre SV, Dos Santos P, Garlid KD. Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mito KATP. Am J Physiol Heart Circ Physiol . 2008;295(3):H953-61.; Garcia-Cardena et al., 1997García-Cardeña G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem . 1997;272(41):25437-40.; Maniatis et al., 2006Maniatis NA, Brovkovych V, Allen SE, John TA, Shajahan AN, Tiruppathi C, et al. Novel mechanism of endothelial nitric oxide synthase activation mediated by caveolae internalization in endothelial cells. Circ Res . 2006;99(8):870-7.). Increased disruption of the caveolin/eNOS complex by calcium/ calmodulin-binding to eNOS leads to an increase in the activity of eNOS (Feron, Balligand, 2006Feron O, Balligand JL. Caveolin and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res . 2006;69(4):788-97.). It has been reported that activation of PKA and Ras-p42/44 MAPK downregulates cav-1 expression (Engelman et al., 1999Engelman JA, Zhang XL, Razani B, Pestell RG, Lisanti MP. p42/44 MAP kinase-dependent and-independent signaling pathways regulate caveolin-1 gene expression. Activation of Ras-MAP kinase and protein kinase a signaling cascades transcriptionally down-regulates caveolin-1 promoter activity. J Biol Chem . 1999;274(45):32333-41.). Moreover, overexpression of cav-3 in myocardium has been reported to mimic preconditioning by activating PI-3K (Tsutsumi et al., 2008Tsutsumi YM, Horikawa YT, Jennings MM, Kidd MW, Niesman IR, Yokoyama U, et al. Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning. Circulation . 2008;118(19):1979-88.).

Role of caveolin in ischemic preconditioning

It has been documented that there is the involvement of caveolins and caveolae in protecting the heart from ischemia/reperfusion injury (Gratton, Bernatchez, Sessa, 2004Gratton JP, Bernatchez P, Sessa WC. Caveolae and caveolins in the cardiovascular system. Circ Res . 2004;94(11):1408-17.; Ajmani et al., 2011Ajmani P, Yadav HN, Singh M, Sharma PL. Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart. BMC Cardiovasc Disord. 2011;11:43.). Caveolae disruption in cardiac myocytes abolished cardiac protection (Patel et al., 2007Patel HH, Tsutsumi YM, Head BP, Niesman IR, Jennings M, Horikawa Y, et al. Mechanisms of cardiac protection from ischemia/reperfusion injury:a role for caveolae and caveolin-1. FASEB J. 2007;21(7):1565-74.). Signaling molecules, as shown in Figure 3 involved in cardiac protection, include GPCRs and the protein tyrosine kinase Src, which compartmentalize within caveolae and interact with the scaffolding domain of caveolin (Krajewska, Maslowska, 2004Krajewska WM, Masłowska I. Caveolins: Structure and function in signal transduction. Cell Mol Biol Lett. 2004;9(2):195-220.). Various GPCRs such as opioids and adenosine promote cardiac protection as well as post-receptor components that can enhance protection localize to caveolae and co-immunoprecipitate with caveolins (Head et al., 2005Head BP, Patel HH, Roth DM, Lai NC, Niesman IR, Farquhar MG, et al. G-protein-coupled receptor signaling components localize in both sarcolemmal and intracellular caveolin-3-associated microdomains in adult cardiac myocytes. J Biol Chem . 2005;280 (35):31036-44.). Further, it has been reported that the infusion of the caveolin scaffolding domain (CSD) peptide of cav-1 into ischemic/reperfused hearts results in the recovery of cardiac function (Young, Ikeda, Lefer, 2001Young LH, Ikeda Y, Lefer AM. Caveolin-1 peptide exert cardioprotective effects in myocardial ischemia-reperfusion via nitric oxide mechanism. Am J Physiol Heart Circ Physiol . 2001;280(6):H2489-95.). Further, treatment with isoflurane modifies cardiac myocytes sarcolemmal structure and composition leads to activation of Src kinase and phosphorylation of cav-1 contributes to cardiac protection (Patel et al., 2007Patel HH, Tsutsumi YM, Head BP, Niesman IR, Jennings M, Horikawa Y, et al. Mechanisms of cardiac protection from ischemia/reperfusion injury:a role for caveolae and caveolin-1. FASEB J. 2007;21(7):1565-74.). It is documented that calmodulin disrupts the heterotrimeric complex formed between eNOS and caveolin in a calcium-dependent manner (Michel et al., 1997Michel JB, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem . 1997;272(25):15583-6.).

FIGURE 3
Caveolin Binding with Signaling Molecules.

Moreover, caveolin (cav-1 and cav-3) maintains eNOS in inactivated state and thereby limits NO production (Maniatis et al., 2006Maniatis NA, Brovkovych V, Allen SE, John TA, Shajahan AN, Tiruppathi C, et al. Novel mechanism of endothelial nitric oxide synthase activation mediated by caveolae internalization in endothelial cells. Circ Res . 2006;99(8):870-7.), but agonist stimulation leads to activation of eNOS through the increase in calcium and disruption of caveolin/eNOS heterocomplex (Feron, Balligand, 2006Feron O, Balligand JL. Caveolin and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res . 2006;69(4):788-97.). It has been reported that activation of PKA and Ras-p42/44 MAPK downregulates cav-1 expression (Engelman et al., 1999Engelman JA, Zhang XL, Razani B, Pestell RG, Lisanti MP. p42/44 MAP kinase-dependent and-independent signaling pathways regulate caveolin-1 gene expression. Activation of Ras-MAP kinase and protein kinase a signaling cascades transcriptionally down-regulates caveolin-1 promoter activity. J Biol Chem . 1999;274(45):32333-41.). Moreover, overexpression of cav-3 in myocardium has been reported to mimic preconditioning by activating PI3K (Tsutsumi et al., 2008Tsutsumi YM, Horikawa YT, Jennings MM, Kidd MW, Niesman IR, Yokoyama U, et al. Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning. Circulation . 2008;118(19):1979-88.). Ischemic preconditioning induces the translocation of eNOS and GLUT-4 to and from the plasma membrane, which is essential for cardioprotection (Koneru et al., 2007Koneru S, Penumathsa SV, Thirunavukkarasu M, Samuel SM, Zhan L, Han Z, et al. Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. Am J Physiol Heart Circ Physiol . 2007;292(5):H2060-72.). However, preconditioning with angiotensin II improves post-ischemic ventricular recovery, reduces myocardial infarction and decreases cardiomyocyte apoptosis (Das, Das, Das, 2007Das M, Das S, Das DK. Caveolin and MAP kinase interaction in angiotensin II preconditioning of the myocardium.J Cell Mol Med. 2007;11(4):788-97.) which is due to decrease association of p38MAPKβ and ERK1/2, i.e., anti-death signalling components with caveolin and increased association with p38MAPKα and JNK, i.e., death signaling components generate survival signal as demonstrated by increased phosphorylation of Akt and enhanced induction of expression of Bcl-2 in the heart (Das, Das, Das, 2007Das M, Das S, Das DK. Caveolin and MAP kinase interaction in angiotensin II preconditioning of the myocardium.J Cell Mol Med. 2007;11(4):788-97.). Moreover, Pharmacological Preconditioning with bradykinin induces the formation of a caveolar signaling platform (signalosomes) that contains the enzymes of the signaling pathway which interact with mitochondria to induce the opening of mito KATP channel (Quinlan et al., 2008Quinlan CL, Costa AD, Costa CL, Pierre SV, Dos Santos P, Garlid KD. Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mito KATP. Am J Physiol Heart Circ Physiol . 2008;295(3):H953-61.).

Mitochondrial KATP and ischemic preconditioning

ATP-Sensitive K+ Channel was first identified in 1983 in the myocardium (Noma, 1983Noma A. ATP-regulated K+ channels in cardiac muscle. Nature . 1983;305(5930):147-8.). Two subtypes of KATP channels have been documented, one is sarcolemmal KATP channel (sarc KATP) which is present on the cell membrane (Aguilar-Bryan et al., 1998Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J. Toward understanding the assembly and structure of KATP channels. Physiol Rev. 1998;78(1):227-45.) while other is located in the inner membrane of the mitochondria and known as mitochondrial ATP sensitive potassium channels (mito KATP) (Yokoshiki et al., 1998Yokoshiki H, Sunagawa M, Seki T, Sperelakis N. ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells. Am J Physiol . 1998;274(1):C25-37.). The KATP channels belong to the ATP-binding cassette transporter superfamily. Sarcolemmal KATP channel is composed of an octameric complex of two types of subunits, the Kir6.2 and the SUR2A subunit whereas mito KATP channel is comprised of two subunits one is a pore-forming, inward-rectifying potassium channel subunit (Kir), and other is regulatory sulfonylurea receptor (SUR) (Mccully, Levitsky, 2003McCully JD, Levitsky S. The mitochondrial K(ATP) channel and cardioprotection. Ann Thorac Surg. 2003;75(2):S667-73.; Mironova et al., 2004Mironova GD, Negoda AE, Marinov BS, Paucek P, Costa AD, Grigoriev SM et al. Functional distinctions between the mitochondrial ATP-dependent K+ channel (mito KATP) and its inward rectifier subunit (mito KIR). J Biol Chem . 2004;279(31):32562-8.).

Mito KATP channel acts as the trigger, as well as the end effector of ischemic preconditioning mediated cardioprotection (Gross, Peart, 2003Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol . 2003;285(3):H921-30.). Moreover, the opening of mito KATP channel leads to an influx of K+ in the mitochondrial matrix (da Silva et al., 2003da Silva MM, Sartori A, Belisle E, Kowaltowski AJ. Ischemic preconditioning inhibits mitochondrial respiration, increases H2O2 release and enhances K+ Transport. Am J Physiol Heart Circ Physiol . 2003;285(1):H154-62.) resulting in depolarised inner mitochondrial membrane and reduced mitochondrial calcium entry into the mitochondria resulting in inhibition of opening of mPTP (Costa et al., 2006Costa AD, Jakob R, Costa CL, Andrukhiv K, West IC, Garlid KD. The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition. J Biol Chem . 2006;281(30):20801-8.; Zoratti et al., 2009Zoratti M, De Marchi U, Gulbins E, Szabo I. Novel channels of the inner mitochondrial membrane. Biochim Biophys Acta . 2009;1787(5):351-63.) consequently decrease in the release of cytochrome C and reduction of apoptotic cell death (Kroemer, Dallaporta, Resche-Rigon, 1998Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol. 1998;60:619-42.; Javadov et al., 2003Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol. 2003;549(Pt 2):513-24.; Hausenloy, Duchen, Yellon, 2003Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischemia-reperfusion injury. Cardiovasc Res . 2003;60(3):617-25.; Hausenloy, Yellon, 2004Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia- reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res . 2004;61(3):448-60.). The influx of K+ facilitates the entry of

weak acids into the mitochondrial matrix and accelerates the process of oxidative phosphorylation (Tanonaka et al., 1999Tanonaka K, Taguchi T, Koshimizu M, Ando T, Morinaka T, Yogo T, et al. Role of an ATP-sensitive potassium channel opener, YM934, in mitochondrial energy production in ischemic/reperfused heart. J Pharmacol Exp Ther . 1999;291(2):710-6.). In addition, the opening of mito KATP channels has been shown to cause partial alkalinization, and a small reduction of transmembrane potential leading to the production of ROS (Penna et al., 2007Penna C, Mancardi D, Rastaldo R, Losano G, Pagliaro P. Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling. Cardiovasc Res . 2007;75(1):168-177.) which mediate the cardioprotective effect of ischemic preconditioning by activation of PKC (Bouwman et al., 2004Bouwman RA, Musters RJ, van Beek-Harmsen BJ, de Lange JJ, Boer C. Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection. Anesthesiology. 2004;100(3):506-14.; Andrukhiv et al., 2006Andrukhiv A, Costa AD, West IC, Garlid KD. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol. 2006;291(5):H2067-74.). Several potassium channel openers such as cromakalim (Grover et al., 1995Grover GJ, D’Alonzo AJ, Parham CS, Darbenzio RB. Cardioprotection with the KATPopener cromakalim is not correlated with ischemic myocardial action potential duration. J Cardiovasc Pharmacol. 1995;26(1):145-52.), bimakalim (Puddu et al., 2006Puddu PE, Garlid KD, Monti F, Iwashiro K, Picard S, Dawodu AA, et al. Bimakalim: A promising KATP Channel Activating Agent. Cardiovasc Drug Rev. 2006;18(1):25-46.), diazoxide (Lawrence et al., 2001Lawrence CL, Billups B, Rodrigo GC, Standen NB. The KATP channel opener diazoxide protects cardiac myocytes during metabolic inhibition without causing mitochondrial depolarization or flavoprotein oxidation. Br J Pharmacol. 2001;134(3):535-42.; Dröse, Brandt, Hanley, 2006Dröse S, Brandt U, Hanley PJ. K+-independent actions of diazoxide question the role of inner membrane KATP channels in mitochondrial cytoprotective signaling. J Biol Chem . 2006;281(33):23733-9.), have been reported to produce cardioprotection against ischemia reperfusion-induced injury. A specific blocker of mito KATP channel, i.e., 5-hydroxy decanoate (Hide, Thiemermann, 1996Hide EJ, Thiemermann, C. Limitation of myocardial infarct size in the rabbit by ischaemic preconditioning is abolished by sodium 5-hydroxydecanoate. Cardiovasc Res . 1996;31(6):941-6.; Yang et al., 2009Yang MK, Lee SH, Seo HW, Yi KY, Yoo SE, Lee BH, et al. KR-31761, a novel K+(ATP) channel opener, exerts cardioprotective effects by opening both Mitochondrial K+(ATP) and sarcolemmal K+(ATP) channels in rat models of ischemia/reperfusion-induced heart injury. J Pharmacol Sci. 2009;109(2):222-32.), has been shown to block the protective effects of ischemic preconditioning in the heart. On the other hand, HMR 1098, a specific blocker of sarc KATP channel, has been demonstrated to abolish the protective effects of ischemic preconditioning (Suzuki et al., 2002Suzuki M, Sasaki N, Miki T, Sakamoto N, Ohmoto-Sekine Y, Tamagawa M, et al. Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest . 2002;109(4):509-16.).

Ischemic preconditioning in postmenopausal heart

It has been reported that men are more susceptible than women to hypertension and cardiovascular diseases (Barrett-Connor, 1997Barrett-Connor E. Sex differences in coronary heart disease: Why are women so superior? the 1995 Ancel Keys Lecture. Circulation. 1997;95(1):252-64.). However, after menopause in women, the risk of ischemic heart disease reaches to the same level as in men of the same age (Clarkson et al., 1997Clarkson TB, Cline JM, Williams JK, Anthony MS. Gonadal hormone substitutes: effects on cardiovascular system. Osteoporos Int. 1997;1:S43-51.; Barrett-Connor, 1997Barrett-Connor E. Sex differences in coronary heart disease: Why are women so superior? the 1995 Ancel Keys Lecture. Circulation. 1997;95(1):252-64.), which indicates that the female sex hormones, particularly estrogen plays a crucial role in reducing the risk of ischemic heart diseases (Sullivan et al., 1998Sullivan JM, Vander Zwaag R, Lemp GF, Hughes JP, Maddock V, Kroetz FW, et al. Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med . 1998;108(3):358-63.; Stampfer, 1995). The dramatic increase in the ischemic heart disease is the leading cause of death in postmenopausal women (Bush et al., 1988Bush TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins, and coronary heart disease in women. Clin Chem. 1988;34(8B):B60-70.) and the estrogen replacement therapy lowers the incidence of cardiovascular events (Stampfer et al., 1985Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med . 1985;313(17):1044-9.; Bush et al., 1987Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, et al. Cardiovascular mortality and non-contraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation . 1987;75:1102-9.). However, several clinical studies failed to demonstrate any cardioprotection from such estrogen replacement therapy (Barrett-Connor, Stuenk el, 1999Barrett-Connor E, Stuenkel C. Hormones and heart disease in women: Heart and Estrogen/Progestin replacement study in perspective. J Clin Endocrinol Metab. 1999;84(6):1848-53.; Rossouw et al., 2002Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.). Rossouw et al., 2002Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33. has been reported that the incidence of ischemic heart disease was increased in women receiving estrogen as compared to those receiving placebo.

Cardiomyocytes from female hearts are more resistant to ischemia-reperfusion-induced injury as a comparison of male hearts (Ranki et al., 2001Ranki HJ, Budas GR, Crawford RM, Jovanovic A. Gender-specific difference in cardiac ATP-sensitive K+ channels. J Am Coll Cardiol . 2001;38(3):906-15.). It has been documented that an increased level of phosphorylated Akt and PKCε are responsible for cardioprotection against I-R induced injury in female hearts (Bae, Zhang, 2005Bae S, Zhang L. Gender Differences in Cardioprotection against ischemia/reperfusion injury in adult rat hearts: focus on Akt and protein kinase C signaling. J Pharmacol Exp Ther. 2005;315(3):1125-35.).

Estrogen deficiency is associated with increased TNF-α level, which may lead to increased myocardial injury after menopause (Liao, Chen, Chen, 2002Liao SL, Chen WY, Chen CJ. Estrogen attenuates tumor necrosis factor-alpha expression to provide ischemic neuroprotection in female rats. Neurosci Lett. 2002;330(2):159-62.). In another study, it has been reported that decreased mitochondrial respiration and increased mPTP opening with aging are responsible for necrotic cell death associated with ischemia/reperfusion injury in postmenopausal women (Machikas et al., 2018Machikas AM, Hunter JC, Lopez V, Korzick DH.Increased mitochondrial permeability transition pore opening dominates ischemia-reperfusion injury in the aged female rat heart. Circ Res . 2018;111:A342.).

Shinmura and coworkers demonstrated that the cardioprotective effect of IPC is lost in ovariectomized rats, which is partly due to impaired phosphorylation and translocation of PKCε to the membrane. Moreover, estrogen replacement or selective activation of PKCε-mediated signaling restores the cardioprotective effect of IPC (Shinmura et al., 2008Shinmura K, Nagai M, Tamaki K, Bolli R. Loss of ischemic preconditioning in ovariectomized rat hearts: possible involvement of impaired protein kinase C epsilon phosphorylation. Cardiovasc Res . 2008;79(3):387-94.).

Montalcini et al. (2007Montalcini T, Gorgone G, Gazzaruso C, Sesti G, Perticone F, Pujia A. Endogenous testosterone and endothelial function in postmenopausal women. Coron Artery Dis. 2007;18(1):9-13.) found that the development of cardiovascular diseases after menopause is not only due to a decrease in estrogen but also due to a decrease in androgen. Furthermore, it has been reported that testosterone enhances estradiol’s cardioprotection in ovariectomized rats, estradiol and testosterone combination protects cardiomyocytes against I-R injury (Liu et al., 2011Liu A, Gao L, Kang S, Liu Y, Xu C, Sun H, et al. Testosterone enhances estradiol’scardioprotection in ovariectomized rats.J Endocrinol. 2011;11:1-34.). It has been well documented that ovariectomy (surgical menopause) reduces the protein expression of eNOS and increases the cav-1 expression subsequently decrease the activation of mito KATP channels in cardiac tissue which is also the main cause of abrogated cardioprotective effect of IPC (Figure 4; Pelligrino et al., 2000Pelligrino DA, Ye S, Tan F, Santizo RA, Feinstein DL, Wang Q. Nitric-oxide-dependent pial arteriolar dilation in the female rat: effects of chronic estrogen depletion and repletion. Biochem Biophys Res Commun . 2000;269(1):165-71.; Goyal, Semwal, Yadav, 2016Goyal A, Semwal BC, Yadav HN. Abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart. Hum Exp Toxicol. 2016;35(6):644-53.) but the chronic estrogen treatment or phytoestrogens like daidzein accompanies restoration of the normal activity of myocardial eNOS (Wang et al., 2002Wang X, Abdel-Rahman AA. Estrogen modulation of eNOS activity and its association with caveolin-3 and calmodulin in rat hearts. Am J Physiol Heart Circ Physiol . 2002;282(6):H2309-15.; Goyal, Semwal, Yadav, 2016Goyal A, Semwal BC, Yadav HN. Abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart. Hum Exp Toxicol. 2016;35(6):644-53.).

FIGURE 4
Role of Caveolin-eNOS and mito-KATP in Normal and Estrogen Deficient Condition.

Endogenous and exogenous estrogen in premenopausal and postmenopausal women, respectively, protects against cardiovascular disease (Stampfer et al., 1991Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the nurses’ health study. N Engl J Med . 1991;325(11):756-62.; Grady et al., 1992Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in a postmenopausal women. Ann Intern Med . 1992;117(12):1016-37.). Estrogen acts as a vasoprotective molecule by increasing the bioavailability of nitric oxide (Best et al., 1998Best PJ, Berger PB, Miller VM, Lerman A. The effect of estrogen a replacement therapy on plasma nitric oxide and endothelin-1 levels in postmenopausal women. Ann Intern Med. 1998;128(4):285-8.; Levin, 2005Levin RE. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol. 2005;19(8):1951-9.). Estrogen upregulates eNOS and downregulates its inhibitory protein cav-1 (Hishikawa et al., 1995Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Up regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett. 1995;36(3)0:291-3.). The cardioprotective effects of estrogen are, in part, mediated by the regulation of TNFα levels in the ischemic heart (Xu et al., 2006Xu Y, Arenas IA, Armstrong SJ, Plahta WC, Xu H, Davidge ST. Estrogen improves cardiac recovery after ischemia/ reperfusion by decreasing tumor necrosis factor-alpha. Cardiovasc Res . 2006;69(4):836-44.). The effect of estrogen on eNOS expression is mediated via estrogen receptors α (ERα) and β (ERβ), which are present on endothelial cells (Gavin et al., 2009Gavin KM, Seals DR, Silver AE, Moreau KL. Vascular Endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab . 2009;94(9):3513-20.).

Activation of eNOS by estrogen has been reported to occur through ERK-1/2 (Chen et al., 1999Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest. 1999;103(3):401-6.) pathway as well as via the phosphatidylinositol 3-kinase (PI3K)/protein kinase (Akt) pathway (Simoncini et al., 2000Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature . 2000;407(6803):538-41.; Hisamoto et al., 2001Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, et al. Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem . 2001;276(5):3459-67.; Haynes et al., 2000Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M,et al. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res . 2000;87(8):677-82.). The recruitment of the latter cascade depends on the ligand-dependent association of ERα with PI3K (Simoncini et al., 2000Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature . 2000;407(6803):538-41.). Akt can be activated by estrogen (Camper-Kirby et al., 2001Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E,et al. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res . 2001;88:1020-7.), which further activates eNOS by phosphorylating it at serine 1177 residue (Fulton et al., 1999Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature . 1999;399(6736):597-601.; Dimmeler et al., 1999Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601-5.). This phosphorylation not only activates eNOS but also increases the efficiency of activation by Ca++/calmadulin (McCabe et al., 2000McCabe TJ, Fulton D, Roman LJ, Sessa WC. Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation. J Biol Chem . 2000;275(9):6123-8.). Thus, estrogen increases the bioavailability of NO and thus results in a decrease in myocardial injury. In addition, 17β-estradiol has been shown to reduce myocardial necrosis in rabbits after ischemia and reperfusion (Hale, Birnbaum, Kloner, 1996Hale SL, Birnbaum Y, Kloner RA. beta-Estradiol, but not alpha-estradiol, reduced myocardial necrosis in rabbits after ischemia and reperfusion. Am Heart J . 1996;132(2 Pt 1):258-62.) and improve recovery of mechanical function following global ischemia in isolated rat hearts (Kolodgie et al., 1997Kolodgie FD, Farb A, Litovsky SH, Narula J, Jeffers LA, Lee SJ, et al. Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized rat. J Mol Cell Cardiol . 1997;29(9):2403-14.; Fraser et al., 1999Fraser H, Davidge ST, Clanachan AS. Enhancement of post-ischemic myocardial function by chronic 17 beta-estradiol treatment: role of alterations in glucose metabolism. J Mol Cell Cardiol . 1999;31(8):1539-49.).

CONCLUSION

The cardioprotective potential of IPC is lost in estrogen deficiency. In this condition, the outcome of I/R injury worsens, and the infarct size limiting effect of IPC is blunted due to the upregulation of caveolin and downregulation of nitric oxide as well as inhibition of mito KATP channel. This may affect the clinical application of IPC in patients with estrogen deficiency or postmenopausal women undergoing cardiac surgery.

Therefore, we can say that by adopting the approaches like inhibiting caveolin, upregulating nitric oxide, and the opening of mito KATP can help in regaining the cardioprotective effect of IPC in postmenopausal or estrogen-deficient condition.

REFERENCES

  • Abete P, Ferrara N, Cioppa A, Ferrara P, Bianco S, Calabrese C, et al. Preconditioning does not prevent postischemic dysfunction in aging heart. J Am Coll Cardiol. 1996;2(7):1777-86.
  • Aguilar-Bryan L, Clement JP, Gonzalez G, Kunjilwar K, Babenko A, Bryan J. Toward understanding the assembly and structure of KATP channels. Physiol Rev. 1998;78(1):227-45.
  • Ajmani P, Yadav HN, Singh M, Sharma PL. Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart. BMC Cardiovasc Disord. 2011;11:43.
  • Ambrosio G, Tritto I. Reperfusion injury: Experimental evidence and clinical implications. Am Heart J. 1999;138(2 Pt 2):S69-75.
  • Anaya-Prado R, Toledo-Pereyra LH, Lentsch AB, Ward PA. Ischemia/reperfusion injury. J Surg Res. 2002;105(2):248-58.
  • Andreotti F, Pasceri V, Hackett DR, Davies GJ, Haider AW, Maseri A. Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction. N Engl J Med. 1996;334(1):7-12.
  • Andrukhiv A, Costa AD, West IC, Garlid KD. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol. 2006;291(5):H2067-74.
  • Anzai T, Yoshikawa T, Asakura Y, Abe S, Akaishi M, Mitamura Het al. Preinfarction angina as a major predictor of left ventricular function and long-term prognosis after first Q wave myocardial infarction. J Am Coll Cardiol . 1995;26(2):319-27.
  • Bae S, Zhang L. Gender Differences in Cardioprotection against ischemia/reperfusion injury in adult rat hearts: focus on Akt and protein kinase C signaling. J Pharmacol Exp Ther. 2005;315(3):1125-35.
  • Baines CP, Goto M, Downey JM. Oxygen radicals released during ischemic preconditioning contribute to cardioprotection in the rabbit myocardium. J Mol Cell Cardiol. 1997;29(1):207-16.
  • Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, et al. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003;92(8):873-80.
  • Baines CP. The Mitochondrial permeability transition pore and ischemia-reperfusion injury. Basic Res Cardiol. 2009;104(2):181-8.
  • Banerjee A, Locke-Winter C, Rogers KB, Mitchell MB, Brew EC, Cairns CB, et al. Preconditioning against myocardial dysfunction after ischemia and reperfusion by an alpha 1-adrenergic mechanism. Circ Res . 1993;73(4):656-70.
  • Barrett-Connor E, Stuenkel C. Hormones and heart disease in women: Heart and Estrogen/Progestin replacement study in perspective. J Clin Endocrinol Metab. 1999;84(6):1848-53.
  • Barrett-Connor E. Sex differences in coronary heart disease: Why are women so superior? the 1995 Ancel Keys Lecture. Circulation. 1997;95(1):252-64.
  • Bartosz G. Reactive oxygen species: destroyers or messengers? BiochemPharmacol. 2009;77(8):1303-15
  • Becker LB. New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res. 2004;61(3):461-70.
  • Belhomme D, Peynet J, Louzy M, Launay JM, Kitakaze M, Menasche, P. Evidence for preconditioning by isoflurane in coronary artery bypass graft surgery. Circulation . 1999;100:II340-4.
  • Bell SP, Sack MN, Patel A, Opie LH, Yellon DM. Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle. J Am Coll Cardiol. 2000;36(7):2296-302.
  • Best PJ, Berger PB, Miller VM, Lerman A. The effect of estrogen a replacement therapy on plasma nitric oxide and endothelin-1 levels in postmenopausal women. Ann Intern Med. 1998;128(4):285-8.
  • Bolli R, Jeroudi MO, Patel BS, DuBose CM, Lai EK, Roberts R, et al. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc Natl Acad Sci U S A. 1989;86(12):4695-9.
  • Bolli R. The early and late phases of preconditioning against myocardial stunning and the essential role of oxyradicals in the late phase: an overview. Basic Res Cardiol . 1996;91(1):57-63.
  • Bouwman RA, Musters RJ, van Beek-Harmsen BJ, de Lange JJ, Boer C. Reactive oxygen species precede protein kinase C-delta activation independent of adenosine triphosphate-sensitive mitochondrial channel opening in sevoflurane-induced cardioprotection. Anesthesiology. 2004;100(3):506-14.
  • Buja LM. Myocardial ischemia and reperfusion injury. Cardiovasc Pathol. 2005;14(4):170-5.
  • Bush TL, Fried LP, Barrett-Connor E. Cholesterol, lipoproteins, and coronary heart disease in women. Clin Chem. 1988;34(8B):B60-70.
  • Bush TL, Barrett-Connor E, Cowan LD, Criqui MH, Wallace RB, Suchindran CM, et al. Cardiovascular mortality and non-contraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation . 1987;75:1102-9.
  • Camper-Kirby D, Welch S, Walker A, Shiraishi I, Setchell KD, Schaefer E,et al. Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circ Res . 2001;88:1020-7.
  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, et al. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998;282(5392):1318-21.
  • Charan K, Goyal A, Gupta JK, Yadav HN. Role of atrial natriuretic peptide in ischemic preconditioning-induced cardioprotection in the diabetic rat heart. J Surg Res . 2016;201(2):272-8.
  • Chen M, Won DJ, Krajewski S, Gottlieb RA. Calpain and mitochondria in ischemia/reperfusion injury. J Biol Chem. 2002;277(32):29181-6.
  • Chen Z, Yuhanna IS, Galcheva-Gargova Z, Karas RH, Mendelsohn ME, Shaul PW. Estrogen receptor mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J Clin Invest. 1999;103(3):401-6.
  • Clarkson TB, Cline JM, Williams JK, Anthony MS. Gonadal hormone substitutes: effects on cardiovascular system. Osteoporos Int. 1997;1:S43-51.
  • Cohen MV, Liu GS, Downey JM. Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits. Circulation . 1991;84(1):341-9.
  • Cohen MV, Philipp S, Krieg T, Cui L, Kuno A, Solodushko V, et al. Preconditioning-mimetics Bradykinin and DADLE Activate PI3-Kinase Through Divergent Pathways. J Mol Cell Cardiol . 2007;42(4):842-51.
  • Collard CD and Gelman S. Pathophysiology, clinical manifestation, and prevention of ischemia-reperfusion injury. Anesthesiology . 2001;94(6):1133-8.
  • Costa AD, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, et al. Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria. Circ Res . 2005;97(4):329-36.
  • Costa AD, Jakob R, Costa CL, Andrukhiv K, West IC, Garlid KD. The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition. J Biol Chem . 2006;281(30):20801-8.
  • da Silva MM, Sartori A, Belisle E, Kowaltowski AJ. Ischemic preconditioning inhibits mitochondrial respiration, increases H2O2 release and enhances K+ Transport. Am J Physiol Heart Circ Physiol . 2003;285(1):H154-62.
  • Das M, Das S, Das DK. Caveolin and MAP kinase interaction in angiotensin II preconditioning of the myocardium.J Cell Mol Med. 2007;11(4):788-97.
  • Detmers PA, Lo SK, Olsen-Egbert E, Walz A, Baggiolini M, Cohn ZA. Neutrophil-activating protein-1/interleukin-8 stimulates the binding activity of the leukocyte adhesion receptor CD11b/CD18 on human neutrophils. J Exp Med. 1999;171(4):1155-62.
  • Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601-5.
  • Diwan V, Kant R, Jaggi AS, Singh N, Singh D. Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem. 2008;315(1-2):195-201.
  • Downey JM, Cohen MV.Reducing infarct size in the setting of acute myocardial infarction. Prog Cardiovasc Dis. 2006;48(5):363-71.
  • Downey M, Cohen MV. Preconditioning: What it is and how it works. Dialogues in Cardiovascular Medicine. 1997;2:179-96.
  • Dreixler JC, Shaikh AR, Shenoy SK, Shen Y, Roth S. Protein kinase C subtypes and retinal ischemic preconditioning. Exp Eye Res.2008;87(4):300-11.
  • Dröse S, Brandt U, Hanley PJ. K+-independent actions of diazoxide question the role of inner membrane KATP channels in mitochondrial cytoprotective signaling. J Biol Chem . 2006;281(33):23733-9.
  • Du YH, Peng J, Huang ZZ, Jiang DJ, Deng HW, Li YJ. Delayed cardioprotection afforded by nitroglycerin is mediated by alpha-CGRP via activation of inducible nitric oxide synthase. Int J Cardiol. 2004;93(1):49-54.
  • Elçioglu KH, Kabasakal L, Cetinel S, Conturk G, Sezen SF, Ayanoğlu-Dülger G. Changes in caveolin -1 expression and vasoreactivity in the aorta and corpus cavernosum of fructose and streptozotocin-induced diabetic rats. Eur J Pharmacol. 2010;642(1-3):113-20.
  • Elimadi A, Sapena R, Settaf A, Le Louet H, Tillement J, Morin D. Attenuation of liver normothermic ischemia-reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative. Biochem Pharmacol . 2001;62(4):509-16.
  • Engelman JA, Zhang XL, Razani B, Pestell RG, Lisanti MP. p42/44 MAP kinase-dependent and-independent signaling pathways regulate caveolin-1 gene expression. Activation of Ras-MAP kinase and protein kinase a signaling cascades transcriptionally down-regulates caveolin-1 promoter activity. J Biol Chem . 1999;274(45):32333-41.
  • Ermak G, Davies KJ. Calcium and oxidative stress: from cell signaling to cell death. Mol Immunol. 2002;38(10):713-21.
  • Ferdinandy P, Schulz R and Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/ reperfusion injury, preconditioning and postconditioning. Pharmacol Rev. 2007;59(4):418-58.
  • Ferdinandy P, Szilvassy Z, Baxter GF. Adaptation to myocardial stress in disease states: is preconditioning a healthy heart phenomenon? Trends Pharmacol Sci. 1998;19(6):223-9.
  • Feron O, Balligand JL. Caveolin and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res . 2006;69(4):788-97.
  • Ford DA. Alterations in myocardial lipid metabolism during myocardial ischemia and reperfusion. Prog Lipid Res. 2002;41(1):6-26.
  • Fraser H, Davidge ST, Clanachan AS. Enhancement of post-ischemic myocardial function by chronic 17 beta-estradiol treatment: role of alterations in glucose metabolism. J Mol Cell Cardiol . 1999;31(8):1539-49.
  • Frassdorf J, Borowski A, Ebel D, Feindt P, Hermes M, Meemann Tet al. Impact of preconditioning protocol on anesthetic-induced cardioprotection in patients having coronary artery bypass surgery. J Thorac Cardiovasc Surg.2009;137(6):1436-42.
  • Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature . 1999;399(6736):597-601.
  • Fulton D, Gratton JP, Sessa WC. Post-translational control of endothelial nitric oxide synthase: why isn’t calcium/calmodulin enough? J Pharmacol Exp Ther . 2001;299(3):818-24.
  • Galagudza MM, Blokhin IO, Shmonin AA, Mischenko KA. Reduction of Myocardial ischemia-reperfusion injury with pre-and postconditioning: molecular mechanism and therapeutic targets. Cardiovasc Hematol Disord Drug Targets. 2008;8(1):47-65.
  • Galbiati F, Engelman JA, Volonte D, Zhang XL, Minetti C, Li M, et al. Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex and t-tubule abnormalities. J Biol Chem . 2001;276(24):21425-33.
  • García-Cardeña G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, et al. Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem . 1997;272(41):25437-40.
  • Garlid KD, Paucek P, Yarov-Yarovoy V, Murray HN, Darbenzio RB, D’Alonzo AJ, et al. Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. Circ Res . 1997;81(6):1072-82.
  • Gasser R, Schafhalter I, Wolff P, Schwarz T, Furschuss W, Klein W. Experimental models and definitions of myocardial ischemia: A review. Int J Angiol. 1994;3:154-6.
  • Gavin KM, Seals DR, Silver AE, Moreau KL. Vascular Endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab . 2009;94(9):3513-20.
  • Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD. Myocardial protection by brief ischemia in noncardiac tissue. Circulation . 1996;94(9):2193-00.
  • Glenney JR Jr. Tyrosine Phosphorylation of a 22-kDa Protein is correlated with transformation by Rous sarcoma virus. J Biol Chem . 1989;264(34):20163-6.
  • Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circulation . 2013;127(1):e6-e245.
  • Goto M, Liu Y, Yang XM, Ardell JL, Cohen MV, Downey JM. Role of bradykinin in protection of ischemic preconditioning in rabbit hearts. Circ Res . 1995;77(3):611-21.
  • Goyal A, Semwal BC, Yadav HN. Abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart. Hum Exp Toxicol. 2016;35(6):644-53.
  • Goyal A, Agrawal N. Ischemicpreconditioning:Interruptionof various disorders. J Saudi Heart Assoc. 2017;29(2):116-27.
  • Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, et al. Hormone therapy to prevent disease and prolong life in a postmenopausal women. Ann Intern Med . 1992;117(12):1016-37.
  • Gratton JP, Bernatchez P, Sessa WC. Caveolae and caveolins in the cardiovascular system. Circ Res . 2004;94(11):1408-17.
  • Gross GJ, Peart JN. KATP channels and myocardial preconditioning: an update. Am J Physiol Heart Circ Physiol . 2003;285(3):H921-30.
  • Grover GJ, D’Alonzo AJ, Parham CS, Darbenzio RB. Cardioprotection with the KATPopener cromakalim is not correlated with ischemic myocardial action potential duration. J Cardiovasc Pharmacol. 1995;26(1):145-52.
  • Gundewar S, Lefer DJ. Sphingolipid therapy in myocardial ischemia reperfusion injury. Biochim Biophys Acta. 2008;1780(3).571-6.
  • Gupta I, Goyal A, Singh NK, Yadav HN, Sharma PL. Hemin, a heme oxygenase-1 inducer, restores the attenuated cardioprotective effect of ischemic preconditioning in isolated diabetic rat heart. Hum Exp Toxicol . 2017;36(8):867-75.
  • Haider AW, Andreotti F, Hackett DR, Tousoulis D, Kluft C, Maseri A, et al. Early spontaneous intermittent myocardial reperfusion during acute myocardial infarction is associated with augmented thrombogenic activity and less myocardial damage. J Am Coll Cardiol . 1995;26(3):662-7.
  • Hale SL, Birnbaum Y, Kloner RA. beta-Estradiol, but not alpha-estradiol, reduced myocardial necrosis in rabbits after ischemia and reperfusion. Am Heart J . 1996;132(2 Pt 1):258-62.
  • Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion - a target for cardioprotection. Cardiovasc Res . 2004;61(3):372-85.
  • Halestrap AP. Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans. 2006;34(Pt 2):232-7.
  • Han S, Huang W, Liu Y, Pan S, Feng Z, Li S. Does leukocyte- depleted blood cardioplegia reduce myocardial reperfusion injury in cardiac surgery? A systematic review and meta- analysis. Perfusion. 2013;28(6):474-83.
  • Hausenloy DJ, Duchen MR, Yellon DM. Inhibiting mitochondrial permeability transition pore opening at reperfusion protects against ischemia-reperfusion injury. Cardiovasc Res . 2003;60(3):617-25.
  • Hausenloy DJ, Yellon DM. New directions for protecting the heart against ischaemia- reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway. Cardiovasc Res . 2004;61(3):448-60.
  • Haynes MP, Sinha D, Russell KS, Collinge M, Fulton D, Morales-Ruiz M,et al. Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ Res . 2000;87(8):677-82.
  • Head BP, Patel HH, Roth DM, Lai NC, Niesman IR, Farquhar MG, et al. G-protein-coupled receptor signaling components localize in both sarcolemmal and intracellular caveolin-3-associated microdomains in adult cardiac myocytes. J Biol Chem . 2005;280 (35):31036-44.
  • Hennan JK, Driscoll EM, Barrett TD, Fischbach PS, Lucchesi BR. Effect of sodium/hydrogen exchange inhibition on myocardial infarct size after coronary artery thrombosis and thrombolysis. Pharmacology. 2006;78(1):27-37.
  • Hide EJ, Thiemermann, C. Limitation of myocardial infarct size in the rabbit by ischaemic preconditioning is abolished by sodium 5-hydroxydecanoate. Cardiovasc Res . 1996;31(6):941-6.
  • Hisamoto K, Ohmichi M, Kurachi H, Hayakawa J, Kanda Y, Nishio Y, et al. Estrogen induces the Akt-dependent activation of endothelial nitric-oxide synthase in vascular endothelial cells. J Biol Chem . 2001;276(5):3459-67.
  • Hishikawa K, Nakaki T, Marumo T, Suzuki H, Kato R, Saruta T. Up regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett. 1995;36(3)0:291-3.
  • Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Ann N Y Acad Sci. 2005;1047:248-58.
  • Insel PA, Head BP, Patel HH, Roth DM, Bundey RA, Swaney JS. Compartmentation of G-protein coupled receptors and their signalling components in lipid rafts and caveolae. Biochem Soc Trans . 2005;33(Pt 5):1131-4.
  • Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol. 2003;549(Pt 2):513-24.
  • Jonassen AK, Mjøs OD, Sack MN. p70S6 Kinase is a functional target of insulin activated Akt cell-survival signalling. Biochem Biophys Res Commun. 2004;315(1):160-5.
  • Joy M, Cairns AW, Sprigings D. Observations on the warm-up phenomenon in angina pectoris. Br Heart J. 1987;58(2):116-21.
  • Kato T, Kamiyama T, Maruyama Y, Tanaka S, Yoshimoto N. Nicorandil, a potent cardioprotective agent, reduces qt dispersion during coronary angioplasty. Am Heart J . 2001;141(6):940-3.
  • Khanna G, Diwan V, Singh M, Singh N, Jaggi AS. Reduction of ischemic, pharmacological and remote preconditioning effects by an antioxidant N-acetyl cysteine pretreatment in isolated rat heart.YakugakuZasshi. 2008;128(3):469-77.
  • Kis A, Yellon DM, Baxter GF. Second window of protection following myocardial preconditioning: an essential role for PI3 kinase and p70S6 kinase. J Mol Cell Cardiol . 2003;35(9):1063-71.
  • Kloner RA, Jennings RB. Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1. Circulation . 2001;104(24):2981-9.
  • Kloner RA, Shook T, Antman EM, Cannon CP, Przyklenk K, Yoo K, et al. Prospective temporal analysis of the onset of preinfarction angina versus outcome: an ancillary study in TIMI-9B. Circulation . 1998;97(11):1042-5.
  • Kloner RA. Does reperfusion injury exist in humans? J Am Coll Cardiol . 1993;21(2):537-45.
  • Kolodgie FD, Farb A, Litovsky SH, Narula J, Jeffers LA, Lee SJ, et al. Myocardial protection of contractile function after global ischemia by physiologic estrogen replacement in the ovariectomized rat. J Mol Cell Cardiol . 1997;29(9):2403-14.
  • Koneru S, Penumathsa SV, Thirunavukkarasu M, Samuel SM, Zhan L, Han Z, et al. Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. Am J Physiol Heart Circ Physiol . 2007;292(5):H2060-72.
  • Korge P, Honda HM, Weiss JN.Protection of cardiac mitochondria by diazoxide and protein kinase C: implications for ischemic preconditioning. Proc Natl Acad Sci U S A . 2002;99(5):3312-7.
  • Krajewska WM, Masłowska I. Caveolins: Structure and function in signal transduction. Cell Mol Biol Lett. 2004;9(2):195-220.
  • Kroemer G, Dallaporta B, Resche-Rigon M. The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol. 1998;60:619-42.
  • Kukreja RC, Salloum F, Das A, Ockaili R, Yin C, Bremer YA, et al. Pharmacological preconditioning with sildenafil: Basic mechanisms and clinical implications. VasculPharmacol. 2005;42(5-6):219-32.
  • Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, et al. Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res . 1993;72(6):1293-9.
  • Lawrence CL, Billups B, Rodrigo GC, Standen NB. The KATP channel opener diazoxide protects cardiac myocytes during metabolic inhibition without causing mitochondrial depolarization or flavoprotein oxidation. Br J Pharmacol. 2001;134(3):535-42.
  • Lee TM, Su SF, Chou TF, Tsai CH. Pharmacologic preconditioning of estrogen by activation of the myocardial adenosine triphosphate-sensitive potassium channel in patients undergoing coronary angioplasty. J Am Coll Cardiol . 2002;39(5):871-7.
  • Leesar MA, Stoddard MF, Xuan YT, Tang XL, Bolli, R. Nonelectrocardiographic evidence that ischemic preconditioning and adenosine preconditioning exist in humans. J Am Coll Cardiol . 2003;42(3):437-45.
  • Levin RE. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol. 2005;19(8):1951-9.
  • Liao SL, Chen WY, Chen CJ. Estrogen attenuates tumor necrosis factor-alpha expression to provide ischemic neuroprotection in female rats. Neurosci Lett. 2002;330(2):159-62.
  • Liu A, Gao L, Kang S, Liu Y, Xu C, Sun H, et al. Testosterone enhances estradiol’scardioprotection in ovariectomized rats.J Endocrinol. 2011;11:1-34.
  • Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation . 1991;84(1):350-6.
  • Liu M, Zhang P, Chen M, Zhang W, Yu L, Yang XC et al. Aging might increase myocardial ischemia/reperfusion- induced apoptosis in humans and rats. Age (Dordr). 2012;34(3):621-32.
  • Lozza G, Conti A, Ongini E, Monopoli A. Cardioprotective effects of adenosine A1and A2A receptor agonists in the isolated rat heart. Pharmacol Res. 1997;35(1):57-64.
  • Machikas AM, Hunter JC, Lopez V, Korzick DH.Increased mitochondrial permeability transition pore opening dominates ischemia-reperfusion injury in the aged female rat heart. Circ Res . 2018;111:A342.
  • Maniatis NA, Brovkovych V, Allen SE, John TA, Shajahan AN, Tiruppathi C, et al. Novel mechanism of endothelial nitric oxide synthase activation mediated by caveolae internalization in endothelial cells. Circ Res . 2006;99(8):870-7.
  • Marber MS, Joy MD, Yellon DM. Is warm-up angina ischemic preconditioning. Br Heart J . 1994;72(3):213-5.
  • Marber MS, Latchman DS, Walker JM, Yellon DM. Cardiac stress protein elevation 24 hours after brief ischemia or heat stress is associated with resistance to myocardial infarction. Circulation . 1993;88(3):1264-72.
  • Marczak J, Nowicki R, Kulbacka J, Saczko J. Is remote ischaemic preconditioning of benefit to patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg. 2012;14(5):634-9.
  • Marczin N, El-Habashi N, Hoare GS, Bundy RE, Yacoub M. Antioxidants in myocardial ischemia-reperfusion injury: therapeutic potential and basic mechanisms. Arch Biochem Biophys. 2003;420(2):222-36.
  • Marina Prendes MG, González M, Savino EA, Varela A. Role of endogenous nitric oxide in classic preconditioning in rat hearts. Regul Pept. 2007;139(1-3):141-5.
  • McCabe TJ, Fulton D, Roman LJ, Sessa WC. Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation. J Biol Chem . 2000;275(9):6123-8.
  • McCully JD, Levitsky S. The mitochondrial K(ATP) channel and cardioprotection. Ann Thorac Surg. 2003;75(2):S667-73.
  • Mentzer RM, Rahko PS, Molina-Viamonte V, Canver CC, Chopra PS, Love RB, et al. Safety, tolerance, and efficacy of adenosine as an additive to blood cardioplegia in humans during coronary artery bypass surgery. Am J Cardiol. 1997;79(12A):38-43.
  • Michel JB, Feron O, Sacks D, Michel T. Reciprocal regulation of endothelial nitric-oxide synthase by Ca2+-calmodulin and caveolin. J Biol Chem . 1997;272(25):15583-6.
  • Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, et al. Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. Nat Genet. 1998;18(4):365-8.
  • Minshall RD, Tiruppathi C, Vogel SM, Malik AB. Vesicle formation and traffickng in endothelial cells and regulation of endothelial barrier function. Histochem Cell Biol. 2002;117(2):105-12.
  • Mironova GD, Negoda AE, Marinov BS, Paucek P, Costa AD, Grigoriev SM et al. Functional distinctions between the mitochondrial ATP-dependent K+ channel (mito KATP) and its inward rectifier subunit (mito KIR). J Biol Chem . 2004;279(31):32562-8.
  • Mitchell MB, Meng X, Ao L, Brown JM, Harken AH, Banerjee A. Preconditioning of isolated rat heart is mediated by protein kinase C. Circ Res . 1995:76(1):73-81.
  • Mocanu MM, Bell RM, Yellon DM. PI3 kinase and not p42/p44 appears to be implicated in the protection conferred by ischemic preconditioning. J Mol Cell Cardiol . 2002;34(6):661-8.
  • Montalcini T, Gorgone G, Gazzaruso C, Sesti G, Perticone F, Pujia A. Endogenous testosterone and endothelial function in postmenopausal women. Coron Artery Dis. 2007;18(1):9-13.
  • Moukarbel GV, Ayoub CM, Abchee AB. Pharmacological therapy for myocardial reperfusion injury. Curr Opin Pharmacol. 2004;4(2):147-53.
  • Murphy E, Steenbergen C. Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 2008;88(2):581-609.
  • Murphy E. Primary and secondary signaling pathways in early preconditioning that converge on the mitochondria to produce cardioprotection. Circ Res . 2004;94(1):7-16.
  • Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation . 1986;74(5):1124-36.
  • Noma A. ATP-regulated K+ channels in cardiac muscle. Nature . 1983;305(5930):147-8.
  • Novgorodov SA, Gudz TI. Ceramide and mitochondria in ischemia/reperfusion. J Cardiovasc Pharmacol . 2009;53(3):198-208.
  • Okamoto T, Schlegel A, Scherer PE, Lisanti MP. Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signalling Complexes” at the Plasma Membrane. J Biol Chem . 1998;273(10):5419-22.
  • Okazaki Y, Kodama K, Sato H, Kitakaze M, Hirayama A, Mishima M et al. Attenuation of increased regional myocardial oxygen consumption during exercise as a major cause of warm-up phenomenon. J Am Coll Cardiol . 1993;21(7):1597-1604.
  • Oldenburg O, Qin Q, Sharma AR, Cohen MV, Downey JM, Benoit JN. Acetylcholine leads to free radical production dependent on K(ATP) channels, G(i) proteins, phosphatidylinositol 3-kinase and tyrosine kinase. Cardiovasc Res . 2002;55(3):544-52.
  • Ostrom RS, Insel PA. The Evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology. Br J Pharmacol . 2004;143(2):235-45.
  • Pachauri P, Garabadu D, Goyal A, Upadhyay PK. Angiotensin (1-7) facilitates cardioprotection of ischemic preconditioning on ischemia-reperfusion-challenged rat heart. Mol Cell Biochem . 2017;430(1-2):99-113.
  • Palade GE. Fine structure of blood capillaries. J Appl Phys. 1953, 24:1424-36.
  • Parratt JR, Kane KA. KATP channels in ischaemic preconditioning. Cardiovasc Res . 1994;28(6):783-7.
  • Patel HH, Murray F, Insel PA. Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol. 2008;48:359-91.
  • Patel HH, Tsutsumi YM, Head BP, Niesman IR, Jennings M, Horikawa Y, et al. Mechanisms of cardiac protection from ischemia/reperfusion injury:a role for caveolae and caveolin-1. FASEB J. 2007;21(7):1565-74.
  • Paz Y, Gurevitch J, Frolkis I, Matsa M, Kramer A, Locker C, et al. Effects of an angiotensin II antagonist on ischemic and nonischemic isolated rat hearts. Ann Thorac Surg . 1998;65(2):474-9.
  • Pelligrino DA, Ye S, Tan F, Santizo RA, Feinstein DL, Wang Q. Nitric-oxide-dependent pial arteriolar dilation in the female rat: effects of chronic estrogen depletion and repletion. Biochem Biophys Res Commun . 2000;269(1):165-71.
  • Penna C, Mancardi D, Rastaldo R, Losano G, Pagliaro P. Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac postconditioning through redox signaling. Cardiovasc Res . 2007;75(1):168-177.
  • Penna C, Mancardi D, Rastaldo R, Pagliaro P. Cardioprotection: a radical view Free radicals in pre and postconditioning. Biochim Biophys Acta . 2009;1787(7):781-93.
  • Ping P, Takano H, Zhang J, Tang XL, Qiu Y, Li RC, et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits: a signaling mechanism for both nitric oxide-induced and ischemia-induced preconditioning. Circ Res . 1999;84(5):587-604.
  • Piper HM, Abdallah Y, Schäfer C. The first minutes of reperfusion: a window of opportunity for cardioprotection. Cardiovasc Res . 2004;61(3):365-71.
  • Powers SK, Murlasits Z, Wu M, Kavazis AN. Ischemia-reperfusion-induced cardiac injury: A brief review. Med Sci Sports Exerc. 2007;39(9):1529-36.
  • Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P.Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation . 1993;87(3):893-9.
  • Przyklenk K, Darling CE, Dickson EW, Whittaker P. Cardioprotection ‘outside the box’the evolving paradigm of remote preconditioning. Basic Res Cardiol . 2003;98(3):149-57.
  • Puddu PE, Garlid KD, Monti F, Iwashiro K, Picard S, Dawodu AA, et al. Bimakalim: A promising KATP Channel Activating Agent. Cardiovasc Drug Rev. 2006;18(1):25-46.
  • Quinlan CL, Costa AD, Costa CL, Pierre SV, Dos Santos P, Garlid KD. Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mito KATP Am J Physiol Heart Circ Physiol . 2008;295(3):H953-61.
  • Ranki HJ, Budas GR, Crawford RM, Jovanovic A. Gender-specific difference in cardiac ATP-sensitive K+ channels. J Am Coll Cardiol . 2001;38(3):906-15.
  • Razani B, Lisanti MP. Two distinct caveolin-1 domains mediate the functional interaction of caveolin-1 with protein kinase A. Am J Physiol Cell Physiol. 2001;281(4):C1241-50.
  • Riess ML, Stowe DF, Warltier DC. Cardiac pharmacological preconditioning with volatile anesthetics: from bench to bedside? Am J Physiol Heart Circ Physiol . 2004;286(5):H1603-7.
  • Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
  • Roth TF, Porter KR. Yolk Protein Uptake in the oocyte of the mosquito aedes aegyti. J Cell Biol. 1964;20(2):313-32.
  • Santos CH, Gomes OM, Pontes JC, Miiji LN, Bispo MA. The ischemic preconditioning and postconditioning effect on the intestinal mucosa of rats undergoing mesenteric ischemia/ reperfusion procedure. Acta Cir Bras. 2008;23(1):22-8.
  • Sato T, O’Rourke B, Marbán E. Modulation of mitochondrial ATP-dependent K+ channels by protein kinase C. Circ Res . 1998;83(1):110-14.
  • Scherer PE, Lewis RY, Volonte D, Engelman JA, Galbiati F, Couet J, et al. Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo. J Biol Chem . 1997;272(46):29337-46.
  • Scherer PE, Lisanti MP, Baldini G, Sargiacomo M, Mastick CC, Lodish HF. Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles. J Cell Biol . 1994;127(5):1233-43.
  • Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol . 2001:281(4);H1630-6.
  • Schultz JE, Rose E, Yao Z, Gross GJ. Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts. Am J Physiol . 1995;268(5 Pt 2):H2157-61.
  • Schulz R, Rose J, Heusch G. Involvement of activation of ATP-dependent potassium channels in ischemic preconditioning in swine. Am J Physiol . 1994;267(4 Pt 2):H1341-52.
  • Segawa D, Sjöquist PO, Wang QD, Gonon A, Nordlander M, Rydén L. Calcium antagonist protects the myocardium from reperfusion injury by interfering with mechanisms directly related to reperfusion: an experimental study with the ultrashort-acting calcium antagonist clevidipine. J Cardiovasc Pharmacol . 2000;36(3):338-43.
  • Sharma S, Singh M, Sharma PL. Beneficial effect of insulin in hyperhomocysteinemia and diabetes mellitus induced vascular endothelium dysfunction: role of phosphoinositide dependent kinase and protein kinase B. Mol Cell Biochem . 2011;348:21-32.
  • Shaul PW, Anderson RG. Role of plasmalemmal caveolae in signal transduction. Am J Physiol . 1998;275(5):L843-51.
  • Shinmura K, Nagai M, Tamaki K, Bolli R. Loss of ischemic preconditioning in ovariectomized rat hearts: possible involvement of impaired protein kinase C epsilon phosphorylation. Cardiovasc Res . 2008;79(3):387-94.
  • Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature . 2000;407(6803):538-41.
  • Sisakiyan H. Pathophysiology, clinical significance and possibilities of cardioprotection in myocardial stunning, hibernation and preconditioning. New Am Med J. 2008;2:28-34.
  • Skyschally A, Gres P, Heusch P, Martin C, Haude M, Erbel R, et al. Preinfarction angina: no interference of coronary microembolization with acute ischemic preconditioning. J Mol Cell Cardiol . 2005;39(2):355-61.
  • Snoeckx LH, van der Vusse GJ, Coumans WA, Willemsen PH, Reneman RS. Differences in ischaemia tolerance between hypertrophied hearts of adult and aged spontaneously hypertensive rats. Cardiovasc Res . 1993;27(5):874-81.
  • Snoeckx LH, van der Vusse GJ, Coumans WA, Willemsen PH, van der Nagel T, Reneman RS. Myocardial function in normal and spontaneously hypertensive rats during reperfusion after a period of global ischemia. Cardiovasc Res .1986;20(1):67-75.
  • Solaini G, Harris DA. Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. Biochem J. 2005;390(Pt 2):377-394.
  • Song KS, Li Shengwen, Okamoto T, Quilliam LA, Sargiacomo M, Lisanti MP. Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J Biol Chem . 1996;271(16):9690-7.
  • Spieker LE, Lüscher TF, Noll G. Current Strategies and perspectives for correcting endothelial dysfunction in atherosclerosis. J Cardiovasc Pharmacol . 2001;38:S35-41.
  • Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the nurses’ health study. N Engl J Med . 1991;325(11):756-62.
  • Stampfer MJ, Willett WC, Colditz GA, Rosner B, Speizer FE, Hennekens CH. A prospective study of postmenopausal estrogen therapy and coronary heart disease. N Engl J Med . 1985;313(17):1044-9.
  • Sullivan JM, Vander Zwaag R, Lemp GF, Hughes JP, Maddock V, Kroetz FW, et al. Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med . 1998;108(3):358-63.
  • Suzuki M, Sasaki N, Miki T, Sakamoto N, Ohmoto-Sekine Y, Tamagawa M, et al. Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. J Clin Invest . 2002;109(4):509-16.
  • Szocs K. Endothelial Dysfunction and reactive oxygen species production in ischemia/reperfusion and nitrite tolerance. Gen Physiol Biophys. 2004;23(3):265-95.
  • Takano H, Tang XL, Qiu Y, Guo Y, French BA, Bolli R. Nitric Oxide donors induce late preconditioning against myocardial stunning and infarction in conscious rabbits via an antioxidant-sensitive mechanism. Circ Res . 1998;83(1):73-84.
  • Tang WH, Wu S, Wong TM, Chung SK, Chung SS. Polyol pathway mediates iron-induced oxidative injury in ischemic- reperfused rat heart. Free Radic Biol Med. 2008;45(5):602-10.
  • Tanonaka K, Taguchi T, Koshimizu M, Ando T, Morinaka T, Yogo T, et al. Role of an ATP-sensitive potassium channel opener, YM934, in mitochondrial energy production in ischemic/reperfused heart. J Pharmacol Exp Ther . 1999;291(2):710-6.
  • Thornton JD, Daly JF, Cohen MV, Yang XM, Downey JM Catecholamines can induce adenosine receptor-mediated protection of the myocardium but do not participate in ischemic preconditioning in the rabbit. Circ Res . 1993;73(4):649-55.
  • Timmers L, Henriques JP, de Kleijn DP, Devries JH, Kemperman H, Steendijk P, et al. Exenatide reduces infarct size and improves cardiac function in a porcine model of ischemia and reperfusion injury. J Am Coll Cardiol . 2009;53(6):501-10.
  • Tomai F, Crea F, Chiariello L, Gioffrè PA. Ischemic preconditioning in humans: models, mediators, and clinical relevance. Circulation . 1999;100(5):559-63.
  • Tomoda H, Aoki N. Comparison of protective effects of preinfarction angina pectoris in acute myocardial infarction treated by thrombolysis versus primary coronary angioplasty with stenting. Am J Cardiol . 1999;84(6):621-5.
  • Tong H, Chen W, Steenbergen C, Murphy E. Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C. Circ Res . 2000;87(4):309-15.
  • Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3beta during preconditioning through a phosphatidylinositol-3-kinase--dependent pathway is cardioprotective. Circ Res . 2002;90(4):377-9.
  • Tong H, Rockman HA, Koch WJ, Steenbergen C, Murphy E. G protein coupled receptor internalization signaling is required for cardioprotection in ischemic preconditioning. Circ Res . 2004;94(8):1133-41.
  • Tsutsumi YM, Horikawa YT, Jennings MM, Kidd MW, Niesman IR, Yokoyama U, et al. Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning. Circulation . 2008;118(19):1979-88.
  • Tyagi P, Tayal G. Ischemic preconditioning of the myocardium. Acta Pharmacol Sin. 2002;23(2):865-70.
  • Vanden Hoek TL, Becker LB, Shao Z, Li C, Schumacker PT.Reactive oxygen species released from mitochondria during brief hypoxia induce preconditioning in cardiomyocytes. J Biol Chem . 1998;273(29):18092-8.
  • Varshney V, Goyal A, Gupta JK, Yadav HN. Role of erythropoietin in ischemic postconditioning induced cardioprotection in hyperlipidemic rat heart. J Indian College Cardiol. 2017;7:72-7.
  • Walker DM, Marber MS, Walker JM, Yellon DM. Preconditioning in isolated superfused rabbit papillary muscles. Am J Physiol . 1994;266(4 Pt 2):H1534-40.
  • Walsh SR, Tang T, Sadat U, Dutka DP, Gaunt ME. Cardioprotection by remote ischemic preconditioning. Br J Anaesth. 2007;99(5):611-6.
  • Wang X, Abdel-Rahman AA. Estrogen modulation of eNOS activity and its association with caveolin-3 and calmodulin in rat hearts. Am J Physiol Heart Circ Physiol . 2002;282(6):H2309-15.
  • Weiland U, Haendeler J, Ihling C, Albus U, Scholz W, Ruetten H, et al. Inhibition of endogenous nitric oxide synthase potentiates ischemia-reperfusion-induced myocardial apoptosis via a caspase-3 dependent pathway. Cardiovasc Res . 2000;45(3):671-8.
  • Williams TM, Lisanti MP. The caveolin genes: from cell biology to medicine. Ann Med. 2004;36(8):584-95.
  • Woolfson RG, Patel VC, Neild GH, Yellon DM. Inhibition of nitric oxide synthesis reduces infarct size by an adenosine-dependent mechanism. Circulation . 1995;91(5):1545-51.
  • Xu B, Zhu GH, Weng JF, Cai WS, Xia JT, Li SH. The roles of caveolin-1and endothelial nitric oxide synthase in the development of portal hypertension in rats with liver cirrhosis. Zhonghua Gan Zang Bing Za Zhi. 2008;16(3):184-7.
  • Xu Y, Arenas IA, Armstrong SJ, Plahta WC, Xu H, Davidge ST. Estrogen improves cardiac recovery after ischemia/ reperfusion by decreasing tumor necrosis factor-alpha. Cardiovasc Res . 2006;69(4):836-44.
  • Yadav HN, Singh M, Sharma PL. Involvement of GSK-3β in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart. Mol Cell Biochem . 2010a;343(1-2):75-81.
  • Yadav HN, Singh M, Sharma PL. Modulation of cardioprotective effect of ischemic preconditioning in hyperlipidaemic rat heart. Eur J Pharmacol . 2010b;643(1):78-83.
  • Yadav HN, Varshney V, Singh NK, Sharma PL. Quercetin: a phytoestrogen attenuate GSK-3b inhibitors induced delayed cardioprotection in diabetic rat heart. Pharmacologia. 2015;6:293-9.
  • Yamada E. The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol. 1955;1(5):445-58.
  • Yan H, Song L, Yang J, Sun Y, Hu D. The association between pre-infarction angina and care-seeking behaviors and its effects on early reperfusion rates for acute myocardial infarction. Int J Cardiol . 2009;135(1):86-92.
  • Yang MK, Lee SH, Seo HW, Yi KY, Yoo SE, Lee BH, et al. KR-31761, a novel K+(ATP) channel opener, exerts cardioprotective effects by opening both Mitochondrial K+(ATP) and sarcolemmal K+(ATP) channels in rat models of ischemia/reperfusion-induced heart injury. J Pharmacol Sci. 2009;109(2):222-32.
  • Yao Z, Gross GJ. A Comparison of adenosine-induced cardioprotection and ischemic preconditioning in dogs. Efficacy, time course, and role of KATP channels. Circulation . 1994;89(3):1229-36.
  • Yao Z, Gross GJ. Role of nitric oxide, muscarinic receptors, and the ATP-sensitive K+ channel in mediating the effects of acetylcholine to mimic preconditioning in dogs. Circ Res . 1993;73(6):1193-201.
  • Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: distant dream or near reality? Heart. 2000;83(4):381-7.
  • Yellon DM, Downey JM. Preconditioning the myocardium from cellular physiology to clinical cardiology. Physiol Rev .2003;83(4):1113-5.
  • Ylitalo K, Niemela M, Linnaluoto M, Valkama J, Mattila K, Peuhkurinen K. Evidence suggesting coronary vasodilatation as the principal mechanism in the warm-up phenomenon. Am Heart J . 2001;141:5A-12A.
  • Ylitalo K, Peuhkurinen K. Adaptation to myocardial ischemia during repeated ventricular pacing in patients with coronary artery disease. Scand Cardiovasc J. 2000;34(2):134-41.
  • Yokoshiki H, Sunagawa M, Seki T, Sperelakis N. ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells. Am J Physiol . 1998;274(1):C25-37.
  • Yoshida H, Kusama Y, Kodani E, Yasutake M, Takano H, Atarashi H et al. Pharmacological preconditioning with bradykinin affords myocardial protection through NO-dependent mechanisms. Int Heart J. 2005;46(5):877-87.
  • Young LH, Ikeda Y, Lefer AM. Caveolin-1 peptide exert cardioprotective effects in myocardial ischemia-reperfusion via nitric oxide mechanism. Am J Physiol Heart Circ Physiol . 2001;280(6):H2489-95.
  • Ytrehus K, Liu Y, Downey JM. Preconditioning protects ischemic rabbit heart by protein kinase C activation. Am J Physiol . 1994;266(3 Pt 2):H1145-52.
  • Zong WX, Thompson CB.Necrotic death as a cell fate. Genes Dev. 2006;20(1):1-15.
  • Zoratti M, De Marchi U, Gulbins E, Szabo I. Novel channels of the inner mitochondrial membrane. Biochim Biophys Acta . 2009;1787(5):351-63.
  • Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90(3):405-13.
  • FINANCIAL/SOURCE OF FUNDS STATEMENT

    There are no funding sources.

Publication Dates

  • Publication in this collection
    04 Nov 2022
  • Date of issue
    2022

History

  • Received
    02 Mar 2020
  • Accepted
    27 July 2020
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br