Cardiac Regeneration using Growth Factors: Advances and Challenges

Abstract

Myocardial infarction is the most significant manifestation of ischemic heart disease and is associated with high morbidity and mortality. Novel strategies targeting at regenerating the injured myocardium have been investigated, including gene therapy, cell therapy, and the use of growth factors. Growth factor therapy has aroused interest in cardiovascular medicine because of the regeneration mechanisms induced by these biomolecules, including angiogenesis, extracellular matrix remodeling, cardiomyocyte proliferation, stem-cell recruitment, and others. Together, these mechanisms promote myocardial repair and improvement of the cardiac function. This review aims to address the strategic role of growth factor therapy in cardiac regeneration, considering its innovative and multifactorial character in myocardial repair after ischemic injury. Different issues will be discussed, with emphasis on the regeneration mechanisms as a potential therapeutic resource mediated by growth factors, and the challenges to make these proteins therapeutically viable in the field of cardiology and regenerative medicine.

Keywords
Myocardial Infarction; Myocardial Ischemia; Vascular Remodeling; Intercellular Signaling Peptides and Proteins; Cell-and Tissue Based Therapy

Resumo

O infarto do miocárdio representa a manifestação mais significativa da cardiopatia isquêmica e está associado a elevada morbimortalidade. Novas estratégias vêm sendo investigadas com o intuito de regenerar o miocárdio lesionado, incluindo a terapia gênica, a terapia celular e a utilização de fatores de crescimento. A terapia com fatores de crescimento despertou interesse em medicina cardiovascular, devido aos mecanismos de regeneração induzidos por essas biomoléculas, incluindo angiogênese, remodelamento da matriz extracelular, proliferação de cardiomiócitos e recrutamento de células-tronco, dentre outros. Em conjunto, tais mecanismos promovem a reparação do miocárdio e a melhora da função cardíaca. Esta revisão pretende abordar o papel estratégico da terapia, com fatores de crescimento, para a regeneração cardíaca, considerando seu caráter inovador e multifatorial sobre o reparo do miocárdio após dano isquêmico. Diferentes questões serão discutidas, destacando-se os mecanismos de regeneração como recurso terapêutico potencial mediado por fatores de crescimento e os desafios para tornar essas proteínas terapeuticamente viáveis no âmbito da cardiologia e da medicina regenerativa.

Palavras-chave
Infarto do Miocárdio; Isquemia Miocárdica; Remodelação Vascular; Peptídeos e Proteínas de Sinalização Intercelular; Terapia Baseada em Transplante de Células e Tecidos

Introduction

Cardiovascular diseases (CVD) are the leading cause of death among men and women worldwide, in all racial and ethnic groups.¹ In the United States, these diseases account for approximately 57% of all deaths in the country.² In Europe, CVD cause 4.3 million deaths every year, which represents almost half (48%) of all deaths in that continent.³ CVD are also the major death cause in Brazil, with a specific mortality rate for ischemic heart diseases of 53.8 deaths for every 100,000 inhabitants.⁴

In the CVD group, coronary artery disease (CAD) and peripheral artery disease (PAD) are significant causes of morbidity and mortality, requiring surgical bypass procedure or angioplasty for thousands of patients. On the other hand, myocardial infarction (MI) is the most important manifestation of ischemic heart disease and is also associated with high morbidity and mortality. Ischemia is responsible for cardiac muscle damage, including the loss of cardiomyocytes. This process leads to a negative cardiac remodeling causing the cardiac tissue with a normal contractile function to be replaced by a non-functional scar tissue. The myocardium then produces a compensatory hypertrophic mechanism against ischemia-induced wound healing. However, the hypertrophy may make the heart susceptible to the onset of arrhythmias, ventricular fibrillation and massive heart attack.^5,6 Although advanced revascularization procedures (angioplasty, catheterization, bypass) have contributed to a marked reduction in mortality for CVD, a significant number of patients are not eligible to these procedures or achieve incomplete revascularization with these interventions. Consequently, many of these patients show persistent symptoms of cardiac ischemia despite intensive medical care. They probably suffer from severe diffuse atherosclerotic disease, which cannot be treated by surgery or angioplasty. Symptomatic obstructive vascular disease leads to claudication, peripheral ischemia, angina and congestive heart failure, significantly limiting the quality of life of these patients.

Treatment of MI includes the use of drugs (antiplatelet agents, oral anticoagulants, nitrates, β-adrenergic blockers, ACE inhibitors, and others), surgical reperfusion and revascularization procedures, and, in more complex cases, heart transplantation. In the past decade, there was growing investigation on new strategies for regeneration of the injured myocardium, including gene therapy,^7,8 cell therapy,^9,10 and the use of growth factors.¹¹ The later has also been investigated for the induction of therapeutic angiogenesis for peripheral arterial disease.¹²

The use of growth factors has aroused interest in cardiovascular medicine because of the direct action of these factors on several cell functions such as adhesion, proliferation, migration, and others. When obstruction of the coronary artery flow occurs, induction of angiogenesis by growth factors represents an important mechanism of myocardial repair and protection under hypoxic conditions, resulting in the formation of new vessels.¹³ Consequently, tissue perfusion increases, ultimately leading to a better cardiac function.

On the other hand, the regenerative potential of growth factors has gained great importance in the context of cell therapy. Studies have demonstrated that the benefits derived from the administration of stem cells in the infarct area result, to a greater extent, from the paracrine effect of the growth factors secreted by the cells implanted than from the direct action of the cells in the infarct tissue.^9,14-16 These factors show the potential of inducing different regeneration mechanisms: positive remodeling of the extracellular matrix, proliferation of adult cardiomyocytes, recruiting/homing of cardiac stem cells, antiapoptotic and/or angiogenic effect.^11,17 Together, these mechanisms may reduce inflammation, fibrosis and inadequate perfusion of the ischemic myocardium, promoting tissue repair and improvement of the cardiac function.⁹

Despite the mechanisms of growth-factor-induced tissue regeneration, the therapeutic potential of these proteins is limited by their short biological half-life, low plasma stability and low specificity to target organs. In fact, Hwang and Kloner administered a cocktail of growth factors in rats intraperitoneally and did not observe benefits in the cardiac function, reduction of the infarct size or increase in vascularization.¹⁸

Thus, the clinical use of growth factors depends on new formulation technologies able to increase their half-lives, keep their bioactivity, and control their local delivery in target tissues. In this context, micro- and nanostructured systems have been used as delivery platforms,^19,20 and are a promising formulation strategy for the therapeutic use of growth factors for cardiac regeneration.¹¹

The objective of this review is to address the strategic role of growth factor therapy for cardiac regeneration, considering its innovative and multifactorial character on cardiac repair after an ischemic injury.

Mechanisms of cardiac regeneration

The innate capacity of the human heart for self-regeneration is not enough to compensate the loss of cardiac muscle after an ischemic injury.⁹ Unlike what is observed with skeletal muscles, in which satellite cells and myoblasts form new myocytes a few days after an injury, cardiomyocytes from the border zone of the infarct rarely divide after an ischemic event.²¹ In a lesion induced by infarct, the heart loses approximately 50 g of muscle, and this can result in the death of 2 billion cardiomyocytes.^22,23 This myocardial aggression triggers and modulates tissue reparative changes, including dilatation, hypertrophy, and formation of a collagen scar.²⁴ In relation to cell renewal, the mechanisms of endogenous repair are not enough to induce significant renewal of the muscle mass lost after the ischemic injury.

Cardiomyocyte proliferation plays a key role in cardiac regeneration in some vertebrates, but the proliferative capacity of these cells is limited in the adult hearts of mammals.²¹ Another potential cell renewal mechanism is the mobilization of progenitor cells from the bone marrow to the ischemic area and their differentiation into functional cardiomyocytes.⁹ However, mobilization and homing of these progenitors are also not enough to induce significant regeneration. The myocardium also shelters a population of resident cardiac stem cells (CSC) with potential to differentiate into cardiomyocytes.^25,26 The CSC seem to account for the baseline turnover of cardiomyocytes. However, this renewal probably occurs at very low rates in the absence of lesion.²⁷

The efficacy of these endogenous mechanisms of tissue repair is limited by the hostile microenvironment of the infarcted myocardium, which is characterized by ischemia, inflammation, fibrosis and inadequate angiogenesis. This microenvironment probably prevents, the CSC activation. On the other hand, excessive inflammation also prevents progenitors mobilization and homing. The formation of fibrotic tissue is necessary to prevent muscle rupture after infarction, but the high level of fibrosis represents an important physical barrier to myocardial cell regeneration.⁹ Therefore, mitigation of this hostile environment should contribute to cardiac repair, especially the reduction of local inflammation, apoptosis and fibrosis, as well as the increase in vascularization in the infarct and peri-infarct areas.

Growth factors inducing regenerative mechanisms

Angiogenesis refers to the development of blood vessels from a pre-existing vascular bed. From the medical point of view, the objective is to stimulate vessel growth in patients with conditions characterized by insufficient blood flow, such as ischemic heart diseases and peripheral vascular diseases.²⁸

As regards the latter aspect, the identification of growth factors that induce the angiogenic process stimulated the interest in the use of these proteins for the induction of therapeutic angiogenesis.¹¹ In the case of myocardial infarction, angiogenic therapy with growth factors may salvage the ischemic tissue at early stages of infarction, by supplying the tissue with new vessels. This process is essential to prevent heart failure through the control of cardiomyocyte hypertrophy and contractility.²⁹ In fact, angiogenesis is the main growth factor-induced reparative mechanism and has been the mechanism most often investigated in experimental studies and clinical trials on injured myocardium repair. Most of these studies have dedicated their efforts toward the angiogenic and regenerative potential of vascular endothelial growth factor (VEGF)^30-33 and fibroblast growth factor (FGF).^31,34-36

Mitigation of the ischemic injury in the cardiac tissue may be induced by antiapoptotic factors, which exert potentially cardioprotective effects. Hepatocyte growth factor (HGF) was first identified as a hepatocyte mitogen, with chemotactic and antiapoptotic actions in different cell types.³⁷ In rats undergoing ischemia and reperfusion, intravenous administration of HGF reduced apoptosis in cardiomyocytes and the infarct size.³⁸ Other antiapoptotic factors with therapeutic potential in cardiac regeneration include platelet-derived growth factor (PDGF-BB)³⁹ and protein thymosin β4⁴⁰, IL-11⁴¹, IL-33⁴², and others.

Endogenous mechanisms mediated by progenitors and stem cells include mobilization and homing of bone marrow progenitors as well as CSC activation. These cells may differentiate into new cardiomyocytes after the ischemic injury, but their number is reduced or they are insufficiently activated to produce significant muscular regeneration. Some proteins show the potential to mobilize bone marrow progenitors to the cardiac lesion area or activate CSC. These properties may be therapeutically explored as regenerative mechanisms activated by growth factors or recombinant proteins, such as the granulocyte colony stimulating factor (G-CSF),⁴³ HGF,⁴⁴ stromal cell-derived factor (SDF-1),⁴⁵ and others.

The paradigm of the heart as a completely differentiated organ was contested based on the identification of mitogens able to induce adult cardiomyocytes to enter into the cell cycle.^46,47 This process opens the possibility to stimulate a new regeneration mechanism in the infarcted heart, leading to the formation of a population of new cardiomyocytes capable of replacing the cell mass lost due to the ischemic injury. Three extracellular factors have been identified for their ability to activate receptors involved in cardiomyocyte proliferation: acidic fibroblast growth factor (FGF-1),⁴⁸ neuregulin (NRG-1),⁴⁷ and periostin.⁴⁹ Treatment of infarcted rats with FGF-1 in combination with a mitogen-activating protein kinase (MAPK) p38 resulted in increased cardiomyocyte mitosis and improved cardiac function.⁵⁰ Studies have demonstrated improved cardiac function in infarcted mice treated with daily injections of NRG-1.^47,51 A summary of growth factor-induced cardiac regeneration mechanisms is shown in Table 1.

Table 1
Main growth factors inducing the mechanisms of cardiac regeneration

Factor	Mechanisms	Reference
VEGF	Angiogenesis	30-33
FGF	Angiogenesis	31,34-36
HGF	Antiapoptosis	37,38, 44
	CSCs chemotaxis
SDF-1	Hematopoietic stem cells mobilization and homing	45
IGF-1	Stem cells and progenitor cells viability and differentiation	52
PDGF	Antiapoptosis	39
G-CSF	Antiapoptosis	43
	Hematopoietic stem cells mobilization and homing
Intermedin	Angiogenesis	53
Angiopoietin	Angiogenesis, remodeling and vascular stabilization	54
Periostin	Cardiomyocyte proliferation	49
Neuregulin-1	Cardiomyocyte proliferation	47
Erythropoietin	Antiapoptosis	55

• VEGF: vascular endothelium growth factor isoforms; FGF: fibroblast growth factor; HGF: Hepatocyte growth factor; SDF-1: stromal cell-derived factor; IGF‑1: Insulin‑like growth factor 1; PDGF: platelet-derived growth factor; G-CSF: granulocyte colony stimulating factor.

Challenges in growth factor formulation

In the past two decades, intensive research on the mechanisms of cardiac regeneration has resulted in considerable advances in the discovery of therapeutic targets related to several growth factors. These proteins have been evaluated in experimental studies and clinical trials, which have demonstrated the safety and potential efficacy of these factors in the treatment of ischemic heart diseases, particularly myocardial infarction.^11,56 However, an important challenge for establishing protein therapy for these diseases is the development of formulation technologies capable of ensuring the reparative mechanisms of these biomolecules and making them clinically viable.

Aspects related to dosage, route of administration, protein stability and biocompatibility should be considered. The ability of these formulations to incorporate multiple factors also represents a critical issue, considering the multifactorial character of the mechanisms involved in myocardial repair following ischemia. Together, these aspects have been previously reviewed and should guide the rational development of growth factor formulations for protein and/or cell therapy focusing on cardiac generation.¹¹

Micro- and nanostructured controlled delivery systems show several advantages over conventional formulations that deliver biopharmaceuticals in their free form, usually in an aqueous vehicle for intravenous administration. By permitting a more adequate pharmacokinetic profile to the effects of the active compound, micro- and nanoformulations facilitate patient's adherence to treatment; provide protection to the active ingredient against enzymatic degradation; permit specific targeting to an organ or target-structure; local and controlled delivery of the molecule of interest. Polymeric systems (hydrogels, scaffolds, micro- and nanoparticles)^11,57,58 and lipid systems (liposomes, solid lipid nanoparticles)^59,60 have been used as cardiac delivery platforms of growth factors, which can be obtained from natural biomaterials (collagen/gelatin, fibrin, hyaluronic acid, alginate, chitosan, etc.) and synthetic materials (polyesters, amino acid polymers, polyacrylamide derivatives, and others).¹¹

Polyesters such as poly (lactic acid-co-glycolic acid, PLGA) and polycaprolactone (PCL) are polymers approved for the use in drug delivery systems because of their low immunogenic potential and adequate biodegradation profile. Previous studies have demonstrated the biocompatibility of PLGA microparticles with the cardiac tissue and the efficacy of these particles as delivery systems of VEGF in the experimental treatment of myocardial infarction.^58,61 Recently, Formiga and colleagues have demonstrated the efficacy of these microparticles as cardiac delivery systems of FGF-1 and NRG-1, ensuring the regenerative effects of these factors in an rat myocardial infarction model.⁶²

Perspectives

Future perspectives for the use of cardioregenerative factors are related to the development of new formulation technologies combined with smart, biocompatible, non-invasive materials. These advances should work as multifunctional structures that combine therapeutic and diagnostic functions in a single micro- or nanostructurated. Additionally, they will allow specific ligand-guided targeting on the material surface. The translational potential of these technologies is predictable, considering the diversity of growth factor-induced regeneration mechanisms. These processes should be explored with more clinical interest both as protein therapy and as adjuvant in stem-cell therapy for cardiac regeneration.

• Sources of Funding
  This study was partially funded by CNPq (461865/2014-9).
• Study Association
  This study is not associated with any thesis or dissertation work.

References

• ¹
  Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442.
• ²
  Rosamond W, Flegal K, Furuie K, Greenlund K, Haase V, Ho M, et al. Heart disease and stroke statistics-2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25-146.
• ³
  British Heart Foundation. European Cardiovascular Disease Statistics 2008. [Accessed in 2015 Nov 12]. Available from: https://www.bhf.org.uk/publications/statistics/european_cardiovascular_disease_statistics_2008
  » https://www.bhf.org.uk/publications/statistics/european_cardiovascular_disease_statistics_2008
• ⁴
  Ministério da Saúde Datasus 2011. Sistema de informações de mortalidade. [Acesso em 2015 Dez 13]. Disponível em: http://tabnet.datasus.gov.br/cgi/tabcgi.exe?idb2012/c08.def
  » http://tabnet.datasus.gov.br/cgi/tabcgi.exe?idb2012/c08.def
• ⁵
  Jugdutt BI. Ischemia/infarction. Heart Fail Clin. 2012;8(1):43-51.
• ⁶
  Zornoff LA, Paiva SA, Duarte DR, Spadaro J. Ventricular remodeling after myocardial infarction: concepts and clinical implications. Arq Bras Cardiol. 2009;92(2):150-6.
• ⁷
  Gaffney MM, Hynes SO, Barry F, O'Brien T. Cardiovascular gene therapy: current status and therapeutic potential. Br J Pharmacol. 2007;152(2):175-88.
• ⁸
  Scimia MC, Gumpert AM, Koch WJ. Cardiovascular gene therapy for myocardial infarction. Expert Opin Biol Ther. 2014;14(2):183-95.
• ⁹
  Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008;451(7181):937-42.
• ¹⁰
  Souza CF, Napoli P, Han SW, Lima VC, Carvalho AC. Células-tronco mesenquimais: células ideais para a regeneração cardíaca? Rev Bras Cardiol Invasiva [on-line]. 2010;18(3):344-53.
• ¹¹
  Formiga FR, Tamayo E, Simon-Yarza T, Pelacho B, Prosper F, Blanco-Prieto MJ. Angiogenic therapy for cardiac repair based on protein delivery systems. Heart Fail Rev. 2012;17(3):449-73.
• ¹²
  Annex BH. Therapeutic angiogenesis for critical limb ischaemia. Nat Rev Cardiol. 2013;10(7):387-96.
• ¹³
  Lee SH, Wolf PL, Escudero R, Deutsch R, Jamieson SW, Thistlethwaite PA. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N Engl J Med. 2000;342(9):626-33.
• ¹⁴
  Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008;103(11):1204-19.
• ¹⁵
  Feng Y, Wang Y, Cao N, Yang H. Progenitor/stem cell transplantation for repair of myocardial infarction: Hype or hope? Ann Palliat Med. 2012;1(1):65-77.
• ¹⁶
  Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol. 2011;50(2):280-9.
• ¹⁷
  Patel AN, Silva F, Winters AA. Stem cell therapy for heart failure. Heart Fail Clin. 2015;11(2):275-86.
• ¹⁸
  Hwang H, Kloner RA. The combined administration of multiple soluble factors in the repair of chronically infarcted rat myocardium. J Cardiovasc Pharmacol. 2011;57(3):282-6.
• ¹⁹
  Vilos C, Velasquez LA. Therapeutic strategies based on polymeric microparticles. J Biomed Biotechnol. 2012;2012:672760.
• ²⁰
  Mundargi RC, Babu VR, Rangaswamy V, Patel P, Aminabhavi TM. Nano/micro technologies for delivering macromolecular therapeutics using poly(D,L-lactide-co-glycolide) and its derivatives. J Control Release. 2008;125(3):193-209.
• ²¹
  Ahuja P, Sdek P, MacLellan WR. Cardiac myocyte cell cycle control in development, disease, and regeneration. Physiol Rev. 2007;87(2):521-44.
• ²²
  Gepstein L. Derivation and potential applications of human embryonic stem cells. Circ Res 2002;91(10):866-76.
• ²³
  Venugopal JR, Prabhakaran MP, Mukherjee S, Ravichandran R, Dan K, Ramakrishna S. Biomaterial strategies for alleviation of myocardial infarction. J R Soc Interface. 2012;9(66):1-19.
• ²⁴
  Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000;101(25):2981-8.
• ²⁵
  Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell. 2003;114(6):763-76.
• ²⁶
  Mayfield AE, Tilokee EL, Davis DR. Resident cardiac stem cells and their role in stem cell therapies for myocardial repair. Can J Cardiol. 2014;30(11):1288-98.
• ²⁷
  Hsieh PC, Segers VF, Davis ME, Macgillivray C, Gannon J, Molkentin JD, et al. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med. 2007;13(8):970-4.
• ²⁸
  Ng YS, D'Amore PA. Therapeutic angiogenesis for cardiovascular disease. Curr Control Trials Cardiovasc Med. 2001;2(6):278-85.
• ²⁹
  Cochain C, Channon KM, Silvestre JS. Angiogenesis in the infarcted myocardium. Antioxid Redox Signal. 2013;18(9):1100-13.
• ³⁰
  Taimeh Z, Loughran J, Birks EJ, Bolli R. Vascular endothelial growth factor in heart failure. Nat Rev Cardiol. 2013;10(9):519-30.
• ³¹
  Atluri P, Woo YJ. Pro-angiogenic cytokines as cardiovascular therapeutics: assessing the potential. BioDrugs. 2008;22(4):209-22.
• ³²
  Testa U, Pannitteri G, Condorelli GL. Vascular endothelial growth factors in cardiovascular medicine. J Cardiovasc Med (Hagerstown). 2008;9(12):1190-221.
• ³³
  Henry TD, Annex BH, McKendall GR, Azrin MA, Lopez JJ, Giordano FJ, et al; VIVA Investigators. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation. 2003;107(10):1359-65.
• ³⁴
  Zhang J, Li Y. Therapeutic uses of FGFs. Semin Cell Dev Biol. 2015 Sept 11 [Epub ahead of print].
• ³⁵
  Unger EF, Goncalves L, Epstein SE, Chew EY, Trapnell CB, Cannon RO 3(rd), et al. Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am J Cardiol. 2000;85(12):1414-9.
• ³⁶
  Simons M, Annex BH, Laham RJ, Kleiman N, Henry T, Dauerman H, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-blind, randomized, controlled clinical trial. Circulation. 2002;105(7):788-93.
• ³⁷
  Boros P, Miller CM. Hepatocyte growth factor: a multifunctional cytokine. Lancet. 1995;345(8945):293-5.
• ³⁸
  Nakamura T, Mizuno S, Matsumoto K, Sawa Y, Matsuda H. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest. 2000;106(12):1511-9.
• ³⁹
  Hsieh PC, Davis ME, Gannon J, MacGillivray C, Lee RT. Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers. J Clin Invest. 2006;116(1):237-48.
• ⁴⁰
  Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature. 2004;432(7016):466-72.
• ⁴¹
  Obana M, Maeda M, Takeda K, Hayama A, Mohri T, Yamashita T, et al. Therapeutic activation of signal transducer and activator of transcription 3 by interleukin-11 ameliorates cardiac fibrosis after myocardial infarction. Circulation. 2010;121(5):684-91.
• ⁴²
  Seki K, Sanada S, Kudinova AY, Steinhauser ML, Handa V, Gannon J, et al. Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling. Circ Heart Fail. 2009;2(6):684-91.
• ⁴³
  Huber BC, Beetz NL, Laskowski A, Ziegler T, Grabmaier U, Kupatt C, et al. Attenuation of cardiac hypertrophy by G-CSF is associated with enhanced migration of bone marrow-derived cells. J Cell Mol Med 2015;19(5):1033-41.
• ⁴⁴
  Madonna R, Cevik C, Nasser M, De Caterina R. Hepatocyte growth factor: molecular biomarker and player in cardioprotection and cardiovascular regeneration. Thromb Haemost. 2012;107(4):656-61.
• ⁴⁵
  Shao S, Cai W, Sheng J, Yin L. Role of SDF-1 and Wnt signaling pathway in the myocardial fibrosis of hypertensive rats. Am J Transl Res. 2015;7(8):1345-56.
• ⁴⁶
  Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabe-Heider F, Walsh S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009;324(5923):98-102.
• ⁴⁷
  Bersell K, Arab S, Haring B, Kuhn B. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell. 2009;138(2):257-70.
• ⁴⁸
  Engel FB, Schebesta M, Duong MT, Lu G, Ren S, Madwed JB, et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev. 2005;19(10):1175-87.
• ⁴⁹
  Kuhn B, Del Monte F, Hajjar RJ, Chang YS, Lebeche D, Arab S, et al. Periostin induces proliferation of differentiated cardiomyocytes and promotes cardiac repair. Nat Med. 2007;13(8):962-9.
• ⁵⁰
  Engel FB, Hsieh PC, Lee RT, Keating MT. FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci USA. 2006;103(42):15546-51.
• ⁵¹
  Liu X, Gu X, Li Z, Li X, Li H, Chang J, et al. Neuregulin-1/erbB-activation improves cardiac function and survival in models of ischemic, dilated, and viral cardiomyopathy. J Am Coll Cardiol. 2006;48(7):1438-47.
• ⁵²
  Dai W, Kloner RA. Cardioprotection of insulin-like growth factor-1 during reperfusion therapy: what is the underlying mechanism or mechanisms? Circ Cardiovasc Interv. 2011;4(4):311-3.
• ⁵³
  Holmes D, Campbell M, Harbinson M, Bell D. Protective effects of intermedin on cardiovascular, pulmonary and renal diseases: comparison with adrenomedullin and CGRP. Curr Protein Pept Sci. 2013;14(4):294-329.
• ⁵⁴
  Chong AY, Caine GJ, Lip GY. Angiopoietin/tie 2 as mediators of angiogenesis: a role in congestive heart failure. Eur J Clin Investig. 2004;34(1):9-13.
• ⁵⁵
  Calvillo L, Latini R, Kajstura J, Leri A, Anversa P, Ghezzi P, Et al. Recombinant human erythropoietin protects the myocardium from ischemia-reperfusion injury and promotes beneficial remodeling. Proc Natl Acad Sci USA. 2003;100(8):4802-6.
• ⁵⁶
  Simón-Yarza T, Formiga F, Tamayo E, Pelacho B, Prosper F, Blanco-Prieto M. Vascular endothelial growth factor-delivery systems for cardiac repair: an overview. Theranostics. 2012;2(6):541-52.
• ⁵⁷
  Rocha Formiga F, Ansorena E, Estella-Hermoso de Mendoza A, Imbuluzqueta E, González D, Blanco-Prieto MJ. Nanosistemas a base de poliésteres. In: Vila Jato JL. (ed). Nanotecnología farmacéutica. Madrid: Real Academia Nacional de Farmacia; 2009. p. 41-101.
• ⁵⁸
  Formiga FR, Pelacho B, Garbayo E, Abizanda G, Gavira JJ, Simon-Yarza T, et al. Sustained release of VEGF through PLGA microparticles improves vasculogenesis and tissue remodeling in an acute myocardial ischemia-reperfusion model. J Control Release. 2010;147(1):30-7.
• ⁵⁹
  Scott RC, Rosano JM, Ivanov Z, Wang B, Chong PL, Issekutz AC, et al. Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function. FASEB J. 2009;23(10):3361-7.
• ⁶⁰
  Zhang S, Uludag H. Nanoparticulate systems for growth factor delivery. Pharm Res. 2009;26(7):1561-80.
• ⁶¹
  Formiga F, Garbayo E, Diaz-Herraez P, Abizanda G, Simón-Yarza T, Tamayo E, et al. Biodegradation and heart retention of polymeric microparticles in a rat model of myocardial ischemia. Eur J Pharm Biopharm. 2013;85(3):665-72.
• ⁶²
  Formiga FR, Pelacho B, Garbayo E, Imbuluzqueta I, Diaz-Herraez P, Abizanda G, et al. Controlled delivery of fibloblast growth factor-1 and neuregulin-1 from biodegradable microparticles promotes cardiac repair in a rat myocardial infarction model through activation of endogenous regeneration. J Control Release. 2014;173:132-9.

Publication Dates

• Publication in this collection
  27 June 2016
• Date of issue
  Sept 2016

History

• Received
  31 Oct 2015
• Reviewed
  18 Mar 2016
• Accepted
  23 Mar 2016