Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review

Borges, Juliana Pereira; Lessa, Marcos Adriano

doi:10.5935/abc.20150024

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Review Article • Arq. Bras. Cardiol. 105 (1) • July 2015 • https://doi.org/10.5935/abc.20150024 copy

Mechanisms Involved in Exercise-Induced Cardioprotection: A Systematic Review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Background:

Acute myocardial infarction is the leading cause of morbidity and mortality worldwide. Furthermore, research has shown that exercise, in addition to reducing cardiovascular risk factors, can also protect the heart against injury due to ischemia and reperfusion through a direct effect on the myocardium. However, the specific mechanism involved in exerciseinduced cardiac preconditioning is still under debate.

Objective:

To perform a systematic review of the studies that have addressed the mechanisms by which aerobic exercise promotes direct cardioprotection against ischemia and reperfusion injury.

Methods:

A search was conducted using MEDLINE, Literatura Latino-Americana e do Caribe de Informação em Ciências da Saúde, and Scientific Electronic Library Online databases. Data were extracted in a standardized manner by two independent researchers, who were responsible for assessing the methodological quality of the studies.

Results:

The search retrieved 78 studies; after evaluating the abstracts, 30 studies were excluded. The manuscripts of the remaining 48 studies were completely read and, of these, 20 were excluded. Finally, 28 studies were included in this systematic review.

Conclusion:

On the basis of the selected studies, the following are potentially involved in the cardioprotective response to exercise: increased heat shock protein production, nitric oxide pathway involvement, increased cardiac antioxidant capacity, improvement in ATP-dependent potassium channel function, and opioid system activation. Despite all the previous investigations, further research is still necessary to obtain more consistent conclusions.

Myocardial Infarction; Exercise/physiology; Myocardial Reperfusion Injury/etiology; Myocardial Ischemia; Heat-Shock Proteins

Author/year	Exercise	Groups	Main outcomes	Conclusion
Nicholson et al. ¹⁹19 Nicholson CK, Lambert JP, Chow CW, Lefer DJ, Calvert JW. Chronic exercise downregulates myocardial myoglobin and attenuates nitrite reductase capacity during ischemia-reperfusion. J Mol Cell Cardiol. 2013;64:1-10./2013	Running wheel 4 weeks	Exe: exercise NO₂: supplemented nitrite Exe + N0₂ Sed: sedentary	Infarcted area and troponin-1: Sed > Exe = Exe + NO₂ > NO₂ Ejection fraction: Sed < Exe = Exe + NO₂ < NO₂ Myoglobin and NFAT: Sed = NO₂ > Exe = Exe + NO₂	Exercise decreases cardiac myoglobin levels by inhibiting the calcineurin-NFAT pathway. Moderate exercise-induced cardioprotection is due to diminished ability to reduce nitrite to NO.
Akita et al. ²⁰20 Akita Y, Otani H, Matsuhisa S, Kyoi S, Enoki C, Hattori R, et al. Exercise-induced activation of cardiac sympathetic nerve triggers cardioprotection via redox-sensitive activation of eNOS and upregulation of iNOS. Am J Physiol Heart Circ Physiol. 2007;292(5):H2051-9./2007	7 consecutive days 60 min/session 60%-70% VO_2max	Exe: exercise Wild: control Phenol: sympathetic ablation Antioxidant supplemented eNOS^(−/−): eNOS knockout 1400W: iNOS blockade iNOS^(−/−): iNOS knockout	Infarcted area: Exe < other groups eNOS and iNOS activity: Exe > other groupsOxidative stress: > in Exe andeNOS^(−/−)	Exercise stimulates cardiac sympathetic innervation, causing eNOS activation with consequent iNOS elevation, which acts as a mediator in late cardioprotection.
Hajnal et al. ¹¹11 Hajnal A, Nagy O, Litvai A, Papp J, Parratt JR, Vegh A. Nitric oxide involvement in the delayed antiarrhythmic effect of treadmill exercise in dogs. Life sci. 2005;77(16):1960-71./2005	1 session 21 min Remaining not reported	CT: control L-NAME CT: eNOS blockade AEST CT: iNOS blockade Exe: exercise Exe + L-NAME Exe + AEST	Arrhythmias: less frequent only in ExeInfarcted area: similar among all groups	NO acts as a catalyst and mediator in exercise-induced late protection against IR injury.
Babai et al. ¹²12 Babai L, Szigeti Z, Parratt JR, Vegh A. Delayed cardioprotective effects of exercise in dogs are aminoguanidine sensitive: possible involvement of nitric oxide. Clin Sci (Lond). 2002;102(4):435-45./2012	1 session 21 min	CT: control without exercise CT + Phe: phenylephrine CT + AG: iNOS blockade Exe 24 h: 24 h after exercise Exe 48 h: 48 h after exercise Exe 24 h + AG: iNOS blockade 24 h after exercise	Baroreflex sensitivity: Exe 24 h and 48 h > other groups Survival: Exe 24 h: 70% and CT: 9%	Exercise-induced cardioprotection is mediated by NO because this effect is abolished by aminoguanidine and iNOS activity increases 24 h after exercise.
Farah et al. ²¹21 Farah C, Kleindienst A, Bolea G, Meyer G, Gayrard S, Geny B, et al. Exercise-induced cardioprotection: a role for eNOS uncoupling and NO metabolites.Basic Res Cardiol. 2013;108(6):389./2013	5 weeks 5 days/week 45 min/session 70% VO2_max25m/min	CT: control Exe: exercise Exe + L-NAME: eNOS blockade Exe + L-NIO: more specific eNOS blockade Exe + BH₄: NO donor	Nitrite and GMPc levels: similar between groups eNOS function: Exe and BH₄ > other groupsInfarcted area: Exe < other groups Oxidative stress: Exe > other groups	Exercise results in increased antioxidant capacity, which prevents an excessive synthesis of NO, limiting its binding to O₂and the consequent formation of peroxynitrite (highly cytotoxic).
Frasier et al. ²²22 Frasier CR, Moukdar F, Patel HD, Sloan RC, Stewart LM, Alleman RJ, et al. Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria. Cardiovasc Res. 2013;98(1):47-55./2013	10 consecutive days 60 min/session 15’ at 15 m/min, 30’ at 30 m/min, and 15’ at 15 m/min	Sed: sedentary Exe: exercise BCNU + Exe: inhibited glutathione reductase Vas2870 + Exe: inhibited NADPH oxidase	Infarcted area and arrhythmias: Exe < other groups Antioxidant activity: Exe > other groups	Adaptive signaling of exercise-induced cardioprotection is triggered by EROS, which increases glutathione reductase activity.
Lee et al. ²³23 Lee Y, Min K, Talbert EE, Kavazis AN, Smuder AJ, Willis WT, et al. Exercise protects cardiac mitochondria against ischemia-reperfusion injury. Med Sci Sports Exerc. 2012;44(3):397-405./2012	5 consecutive days 60 min/session 70% VO2_max30m/min	CP: sedentary without IR CIR: sedentary with IR EP: exercise without IR EIR: exercise with IR	Proapoptotic proteins and EROS: CIR > other groups Functional parameters: CP = EP > EIR > CIR Respiratory function: EIR = CP = EP	Cardioprotection is partially mediated by beneficial adaptations in mitochondrial phenotype, increasing their resistance to the oxidative damage due to IR injury.
Kavazis et al. ²⁴24 Kavazis AN, McClung JM, Hood DA, Powers SK. Exercise induces a cardiac mitochondrial phenotype that resists apoptotic stimuli. Am J Physiol Heart Circ Physiol, 2008;294(2):H928-35./2008	5 consecutive days 60 min/session 30 m/min	Sed: sedentary Extr: trained	Antioxidant enzymes and mitochondrial function: ExTr > Sed Expression of proapoptotic proteins: Sed > ExTr	Exercise induces mitochondrial adaptations that contribute to cardioprotection.
French et al. ¹³13 French JP, Hamilton KL, Quindry JC, Lee Y, Upchurch PA, Powers SK. Exercise-induced protection against myocardial apoptosis and necrosis: MnSOD, calcium-handling proteins, and calpain. Faseb J. 2008;22(8):2862-71./2008	3 consecutive days 60 min/session 30 m/min	C: sedentary T: trainedT-AS: trained with anti-MnSOD treatment T-M: trained with sham anti-MnSOD treatment	MnSOD: T and T-M > T-AS = C Catalase and GPX: similar among groupsInfarcted area and apoptosis: C > T-AS > T = T-M	Exercise increases the activity of antioxidant enzymes (SOD) that promote cardioprotection by attenuating necrosis/apoptosis
Lennon et al. ¹⁶16 Lennon SL, Quindry JC, Hamilton KL, French JP, Hughes J, Mehta JL, et al. Elevated MnSOD is not required for exercise-induced cardioprotection against myocardial stunning. Am J Physiol Heart Circ Physiol. 2004;287(2):H975-80./2004	3 consecutive days 60 min/session 30 m/min	S-C: sedentary control E-C: trained without treatment E-AS: trained with anti-MnSOD treatment E-MM: trained with sham anti-MnSOD treatment	MnSOD: E-C = E-MM > E-AS = S-C Antioxidant activity: catalase > in E groupsDouble product: S-C < other groups	Prevention of exercise-induced elevation of an antioxidant enzyme (MnSOD) does not abolish cardioprotection.
Hamilton et al. ¹⁴14 Hamilton KL, Staib JL, Phillips T, Hess A, Lennon SL, Powers SK. Exercise, antioxidants, and HSP72: protection against myocardial ischemia/reperfusion. Free radic Biol Med. 2003;34(7):800-9./2003	5 consecutive days 60 min/session 30 m/min	Untrained control (1) Untrained and antioxidant diet (2) Trained and antioxidant diet (3) Trained and antioxidant diet (4)	Infarcted area: 1 > 2 = 3 = 4 Antioxidant activity: 1 = 3 < 2 = 4 HSP72/73: 3 > 1 = 2 = 4 Intraventricular pressure: 4 > 3 > 2 > 1	Exercise and use of antioxidants can promote cardioprotection independently and the combination of these two strategies does not interfere in the response.
Hamilton etal. ²⁵25 Hamilton KL, Powers SK, Sugiura T, Kim S, Lennon S, Tumer N, et al. Short-term exercise training can improve myocardial tolerance to I/R without elevation in heat shock proteins. Am J Physiol Heart Circ Physiol. 2001;281(3):H1346-52./2001	3-5 days 60 min/session70% VO_2max 30 m/min	C: control E-cold: exercised at 4°C E-warm: exercised at 25°C	Intraventricular pressure and MnSOD: E-cold = E-warm > C HSPs: E-warm > E-cold = C GPx: E-cold > E-warm = C	The protection is not dependent on increased myocardial HSP levels [Remark 1] but rather on increased myocardial antioxidant defense.
Yamashita et al. ¹⁵15 Yamashita N, Hoshida S, Otsu K, Asahi M, Kuzuya T, Hori M. Exercise provides direct biphasic cardioprotection via manganese superoxide dismutase activation. J Exp Med. 1999;189(11):1699-706./1999	1 session 25-30 min 27-30 m/min	C: controlEx: exercised (0.5h, 3 h, 24 h, 36 h, 48 h, 60h, and 72 h after exercise)	Infarcted area: C = 3 h = 24 h = 72 h > 0.5 h = 36 h = 48 h = 60 h MnSOD activity: 0.5 h = 48 h > other groupsExpression of MnSOD: 48 h > other groups	The exercise-induced production of EROS, TNF-a, and IL-ip results in MnSOD activation, which plays an important role in biphasic cardioprotection against IR injury.
Esposito et al. ²⁶26 Esposito F, Ronchi R, Milano G, Margonato V, Di Tullio S, Marini M, et al. Myocardial tolerance to ischemia-reperfusion injury, training intensity and cessation. Eur J Appl Physiol. 2011;111(5):859-68./2011	10 weeks 3 days/week 60 min/session 60% or 80% VO_2max	UNT: untrained Low: low-intensity exercise High: high-intensity exercise High-det: untrained after high-intensity exercise	Infarcted area: High < Low = High-det < UNT HSP70 and MnSOD: High > Low > High-det > UNT	The cardioprotective benefits of exercise are proportional to its intensity and occur via HSPs and antioxidant defense.
Lennon et al. ²⁷27 Lennon SL, Quindry JC, French JP, Kim S, Mehta JL, Powers SK. Exercise and myocardial tolerance to ischaemia-reperfusion. Acta Physiol Scand.2004; 182(2):161-9./2004	3 consecutive days 60 min/session 55% or 75% VO_2max	C: sedentary control Mod: exercise at 55% VO_2maxHigh: exercise at 75% VO_2max	Cardiac function: High = Mod > C MnSOD: High > Mod = C HSP72: High > Mod > C	Moderate- and high-intensity exercise promotes similar protection against IR injury.
Murlasits et al. ²⁸28 Murlasits Z, Lee Y, Powers SK. Short-term exercise does not increase ER stress protein expression in cardiac muscle. Med Sci Sports Exerc. 2007;39(9):1522-8./2007	5 consecutive days 60 min/session 70% VO_2max	C: sedentary control Trained	Infarcted area: C > Trained HSP72: Trained > C Grp78, Grp94, calreticulin, ATF3, CHOP, Caspase 12, Noxa, Puma: Trained = C	The cardioprotective effect of short-duration exercise is not associated with the regulation of stress proteins such as HSPs.
Quindry et al. ²⁹29 Quindry JC, Hamilton KL, French JP, Lee Y, Murlasits Z, Tumer N, et al. Exercise-induced HSP-72 elevation and cardioprotection against infarct and apoptosis. J Appl Physiol (1985). 2007;103(3):1056-62./2007	3 consecutive days 60 min/session 30 m/min	Sed: sedentary W Ex: exercised at 22°C C Ex: exercised at 8°C	Infarcted area and Tunnel: Sed > W Ex = C Ex HSP72: W Ex > C Ex = Sed	The exercise-induced increase in HSP72 levels is not essential for protection against infarction and apoptosis.
Starnes et al. ³⁰30 Starnes JW, Taylor RP, Ciccolo JT. Habitual low-intensity exercise does not protect against myocardial dysfunction after ischemia in rats. Eur J Cardiovasc Prev Rehabil. 2005;12(2):169-74./2005	16 weeks 5 days/week 40 min/session 55%-60% VO_2max	Sed: sedentary RUN: exercised	Cardiac function: Sed = RUN HSP70: RUN > Sed	Exercise at 55%-60% of VO_2max induces an increase in HSP70 levels, but this increase is below the threshold for inducing cardioprotection.
Moran et al. ³¹31 Morán M, Blazquez I, Saborido A, Megias A. Antioxidants and ecto-5'-nucleotidase are not involved in the training-induced cardioprotection against ischaemia-reperfusion injury. Exp Physiol. 2005;90(4):507-17./2005	24 weeks 5 days/week45 min/session25 m/min	Sed: sedentary Tr: trained	HSP72: Tr > Sed Oxidative stress and adenosine: Tr = SedMnSOD and GR: Tr < Sed	Exercise-induced cardioprotection occurs via increase in HSP72 levels and not through the increase of antioxidant or adenosine levels.
Lennon et al. ³²32 Lennon SL, Quindry J, Hamilton KL, French J, Staib J, Mehta JL, et al. Loss of exercise-induced cardioprotection after cessation of exercise. J Appl Physiol (1985). 2004;96(4):1299-305./2004	3 consecutive days 60 min/session 70% VO_{2 max}	CT: control 1, 3, 9, and 18 days after exercise	Catalase and HSP72: 1 day = 3 days > other groups Cardiac function: 1 day = 3 days = 9 days > 18 days = CT	Cardioprotection is abolished 18 days after the end of exercise and is not related to HSP72 and catalase.
Harris et al. ³³33 Harris MB, Starnes JW. Effects of body temperature during exercise training on myocardial adaptations. Am J Physiol Heart Circ Physiol. 2001;280(5):H2271-80./2001	3, 6, and 9 weeks 5 days/week 60 min/session 23°C or 8°C	Sed: sedentary 3WK, 6WK, and 9WK: exercised for 3/6/9 weeks at 23°C 3WKC, 6WKC, and 9WKC: exercised for 3/6/9 weeks at 8°C	HSP70: 3WK = 6WK = 9WK > CT = 3WKC = 6WKC = 9WKC Cardiac function: 9WK > SED = 9WKC SOD: 9WK = 9WKC	Exercise-induced cardioprotection appears to be due to the increase in HSP70 levels.
Taylor et al. ¹⁰10 Taylor RP, Harris MB, Starnes JW. Acute exercise can improve cardioprotection without increasing heat shock protein content. Am J Physiol Heart Circ Physiol. 1999;276(3 Pt 2):H1098-102./1999	1 or 3 days, 100 min/ day, 20 m/min at 23°C 1 day, 100 min/day, 20 m/min at 8°C	CTRL: sedentary control HS: sedentary heated to 42°C 1DR and 3DR: exercised for 1/3 days at 23°C1CR: exercised for 1 day at 8°C	Cardiac function: CTRL < other groupsHSP72: 1DR = 3DR = HS > 1CR = CTRL	Acute exercise can produce cardioprotective response without increase in HSP72 levels.
Quindry et al. ³⁴34 Quindry JC, Miller L, McGinnis G, Kliszczewicz B, Irwin JM, Landram M, et al. Ischemia reperfusion injury, KATP channels, and exercise-induced cardioprotection against apoptosis. J Appl Physiol (1985). 2012;113(3):498-506./2012	3 days 60 min/session^{70% VO}2max30 m/min	Sed: sedentary control Exe: exercised Ex5HD: exercised with mitochondrial KATP blockade ExHMR: exercised with sarcolemmal KATP blockade	Infarcted area: Exe = Ex5HD < ExHMR = Sed MnSOD: Sed < other groups	Sarcolemmal KATP channels are more important than mitochondrial KATP channels in the prevention of tissue death after exercise.
Quindry et al. ³⁵35 Quindry JC, Schreiber L, Hosick P, Wrieden J, Irwin JM, Hoyt E. Mitochondrial KATP channel inhibition blunts arrhythmia protection in ischemic exercised hearts. Am J Physiol Heart Circ Physiol. 2010;299(1):H175-83./2010	3 consecutive days 60 min/session 30 m/min	Sed: sedentary control Exe: exercised Ex5HD: exercised with mitochondrial KATP blockade ExHMR1098: exercised with sarcolemmal KATP blockade	Arrhythmias: Ex = ExHMR1098 < Ex5HD = Sed MnSOD: Sed < other groups	Mitochondrial KATP channels promote antiarrhythmic protection as part of exercise-induced cardioprotection.
Brown et al. ³⁶36 Brown DA, Chicco AJ, Jew KN, Johnson MS, Lynch JM, Watson PA, et al. Cardioprotection afforded by chronic exercise is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel in the rat. J Physiol. 2005;569(Pt 3):913-24./2005	12 weeks Remaining not informed	Sed: sedentary Tr: trained 5HD: exercised with mitochondrial KATP blockadeHMR1098: exercised with sarcolemmal KATP blockade	Infarcted area: HMR1098 > other groupsCalcium content: 5HD > other groups Blood pressure: 5HD < other groups	Exercise increases the expression of sarcolemmal KATP channels, which when blocked, annuls the cardioprotective benefits of exercise.
Michelsen et al. ³⁷37 Michelsen MM, Stottrup NB, Schmidt MR, Lofgren B, Jensen RV, Tropak M, et al. Exercise-induced cardioprotection is mediated by a bloodborne, transferable factor. Basic Res Cardiol.2012;107(3):260./2012	Bicycle 1 session 25 min 4x 2’ 400W + 3’ 250W	ExPC: exercise-induced preconditioning ExPC + N: exercise-induced preconditioning + opioid blockade rIPC: Remote ischemic preconditioning rIPC + N: Remote ischemic preconditioning + opioid blockade	Infarcted area: rIPC < rIPC + N / ExPC < ExPC + N Blood pressure: rIPC > rIPC + N = ExPC > ExPC + N	Exercise remotely preconditions the heart through the opioid receptor activation-dependent humoral effector.
Galvao et al. ³⁸38 Galvão TF, Matos KC, Brum PC, Negrao CE, Luz PL, Chagas AC. Cardioprotection conferred by exercise training is blunted by blockade of the opioid system. Clinics (Sao Paulo). 2011;66(1):151-7./2011	12 weeks 5 days/week 60 min/sessionn60% VO_2max	C: control ET: physical training M: morphine IR: ischemia and reperfusion M + N: opioid blockade ET + M ET + N	Infarcted area: C, M + N, and ET + N > other groups Intraventricular pressure and capillary density: similar between groups	The chronic effect of exercise in reducing the infarcted area is due to the activation of opioid receptors rather than to increased myocardial perfusion.
Dickson et al. ⁹9 Dickson EW, Hogrefe CP, Ludwig PS, Ackermann LW, Stoll LL, Denning GM. Exercise enhances myocardial ischemic tolerance via an opioid receptor-dependent mechanism. Am J Physiol Heart Circ Physiol.2008;294(1):H402-8./2008	1 session 25 min 25 m/min	Exe: exercise Exe N: exercise with opioid blockade	Intraventricular pressure: equal between groups Infarcted area: Exe < Exe + N	Cardioprotection is mediated by an opioid receptor-dependent mechanism.

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