We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Growth factors: avenues for the treatment of myocardial infarction and potential delivery strategies

    Demin Li

    Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China

    Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China

    Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China

    ,
    Kang Tian

    Department of Bone and Joint, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116000, China

    ,
    Jiacheng Guo

    Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China

    Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China

    Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China

    ,
    Qiguang Wang

    National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, 610065, China

    ,
    Zhen Qin

    Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China

    Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China

    Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China

    ,
    Yongzheng Lu

    Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China

    Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China

    Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China

    ,
    Yanyan Xu

    Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China

    Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China

    Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China

    ,
    Nicola Scott

    Department of Medicine, Christchurch Heart Institute, University of Otago, Christchurch, 8011, New Zealand

    ,
    Chris J Charles

    Department of Orthopedic Surgery and Musculoskeletal Medicine, Christchurch Regenerative Medicine and Tissue Engineering Group, University of Otago, Christchurch, 8011, New Zealand

    ,
    Guozhen Liu

    School of Life and Health Sciences, Chinese University of Hong Kong (Shenzhen), Shenzhen, Guangdong, 518172, China

    ,
    Jinying Zhang

    *Author for correspondence:

    E-mail Address: jyzhang@zzu.edu.cn

    Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China

    Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China

    Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China

    ,
    Xiaolin Cui

    **Author for correspondence:

    E-mail Address: steven.cui@otago.ac.nz

    Department of Bone and Joint, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116000, China

    Department of Orthopedic Surgery and Musculoskeletal Medicine, Christchurch Regenerative Medicine and Tissue Engineering Group, University of Otago, Christchurch, 8011, New Zealand

    &
    Junnan Tang

    ***Author for correspondence:

    E-mail Address: fcctangjn@zzu.edu.cn

    Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China

    Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan, 450052, China

    Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan, 450052, China

    Published Online:https://doi.org/10.2217/rme-2022-0007

    Acute myocardial infarction (AMI) is one of the leading causes of death worldwide. Despite recent advances in clinical management, reoccurence of heart failure after AMI remains high, in part because of the limited capacity of cardiac tissue to repair after AMI-induced cell death. Growth factor-based therapy has emerged as an alternative AMI treatment strategy. Understanding the underlying mechanisms of growth factor cardioprotective and regenerative actions is important. This review focuses on the function of different growth factors at each stage of the cardiac repair process. Recent evidence for growth factor therapy in preclinical and clinical trials is included. Finally, different delivery strategies are reviewed with a view to providing workable strategies for clinical translation.

    Plain language summary

    Acute myocardial infarction is a serious, life-threatening disease. Current treatments for acute myocardial infarction are unsatisfactory, and new treatments are required. Growth factors are promising treatments for myocardial infarction. It is intriguing to understand how growth factors provide cardioprotective benefits. This article describes the various growth factors used to treat myocardial infarction and how they are delivered to the infarcted heart.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Shi N, Mei X, Chen SY. Smooth muscle cells in vascular remodeling. Arterioscler. Thromb. Vasc. Biol. 39(12), e247–e252 (2019).
    • 2. Liu L, Song S, Zhang YP et al. Amphiregulin promotes cardiac fibrosis post myocardial infarction by inducing the endothelial-mesenchymal transition via the EGFR pathway in endothelial cells. Exp. Cell Res. 390(2), 111950 (2020).
    • 3. Wu QQ, Xiao Y, Yuan Y et al. Mechanisms contributing to cardiac remodelling. Clin. Sci. (Lond.) 131(18), 2319–2345 (2017).
    • 4. Nallamothu BK, Bradley EH, Krumholz HM. Current concepts – time to treatment in primary percutaneous coronary intervention. N. Engl. J. Med. 357(16), 1631–1638 (2007).
    • 5. Dangas G, Iakovou I, Nikolsky E et al. Contrast-induced nephropathy after percutaneous coronary interventions in relation to chronic kidney disease and hemodynamic variables. Am. J. Cardiol. 95(1), 13–19 (2005).
    • 6. Best PJM, Lennon R, Ting HH et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J. Am. Coll. Cardiol. 39(7), 1113–1119 (2002).
    • 7. Taylor DA, Zenovich AG. Cardiovascular cell therapy and endogenous repair. Diabetes Obes. Metab. 10, 5–15 (2008).
    • 8. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 126(5), 551–568 (2012).
    • 9. Ye L, Haider HK, Tan R et al. Transplantation of nanoparticle transfected skeletal myoblasts overexpressing vascular endothelial growth factor-165 for cardiac repair. Circulation 116(11 Suppl.), I113–I120 (2007).
    • 10. Tang JN, Cui XL, Caranasos TG et al. Heart repair using nanogel-encapsulated human cardiac stem cells in mice and pigs with myocardial infarction. ACS Nano 11(10), 9738–9749 (2017).
    • 11. Li TS, Cheng K, Malliaras K et al. Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells. J. Am. Coll. Cardiol. 59(10), 942–953 (2012).
    • 12. Fisher SA, Zhang HJ, Doree C, Mathur A, Martin-Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst. Rev. 2015(9), CD006536 (2015).
    • 13. Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst. Rev. 12(12), CD007888 (2016).
    • 14. Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS. Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem. Soc. Trans. 33, 1526–1530 (2005).
    • 15. Heslop JA, Hammond TG, Santeramo I et al. Concise review: workshop review: understanding and assessing the risks of stem cell-based therapies. Stem Cells Transl. Med. 4(4), 389–400 (2015).
    • 16. Malliaras K, Li TS, Luthringer D et al. Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 125(1), 100–112 (2012).
    • 17. Shamsul BS, Aminuddin BS, Ng MHA, Ruszymah BHI. Age and gender effect on the growth of bone marrow stromal cells in vitro. Med. J. Malaysia 59(Suppl. B), 196–197 (2004).
    • 18. Conley SM, Hickson LJ, Kellogg TA et al. Human obesity induces dysfunction and early senescence in adipose tissue-derived mesenchymal stromal/stem cells. Front. Cell Dev. Biol. 8, 197 (2020).
    • 19. Lefer DJ, Marban E. Is cardioprotection dead? Circulation 136(1), 98–109 (2017). •• Comprehensively summarized the treatment of acute myocardial infarction (AMI).
    • 20. Tang XL, Rokosh G, Sanganalmath SK et al. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with a 30-day-old infarction. Circulation 121(2), 293–305 (2010).
    • 21. Cui X, Tang J, Hartanto Y et al. NIPAM-based microgel microenvironment regulates the therapeutic function of cardiac stromal cells. ACS Appl. Mater. Interfaces 10(44), 37783–37796 (2018).
    • 22. Li Q, Hou H, Li M et al. CD73(+) mesenchymal stem cells ameliorate myocardial infarction by promoting angiogenesis. Front. Cell Dev. Biol. 9, 637239 (2021).
    • 23. Nagaya N, Kangawa K, Itoh T et al. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 112(8), 1128–1135 (2005).
    • 24. Mathieu M, Bartunek J, El Oumeiri B et al. Cell therapy with autologous bone marrow mononuclear stem cells is associated with superior cardiac recovery compared with use of nonmodified mesenchymal stem cells in a canine model of chronic myocardial infarction. J. Thorac. Cardiovasc. Surg. 138(3), 646–653 (2009).
    • 25. Askari AT, Unzek S, Popovic ZB et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362(9385), 697–703 (2003).
    • 26. Urbich C, Aicher A, Heeschen C et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J. Mol. Cell. Cardiol. 39(5), 733–742 (2005).
    • 27. Shintani Y, Fukushima S, Varela-Carver A et al. Donor cell-type specific paracrine effects of cell transplantation for post-infarction heart failure. J. Mol. Cell. Cardiol. 47(2), 288–295 (2009).
    • 28. Fei Q, Ma H, Zou J et al. Metformin protects against ischaemic myocardial injury by alleviating autophagy-ROS-NLRP3-mediated inflammatory response in macrophages. J. Mol. Cell. Cardiol. 145, 1–13 (2020).
    • 29. Ong SB, Hernandez-Resendiz S, Crespo-Avilan GE et al. Inflammation following acute myocardial infarction: multiple players, dynamic roles, and novel therapeutic opportunities. Pharmacol. Ther. 186, 73–87 (2018).
    • 30. Zou J, Fei Q, Xiao H et al. VEGF-A promotes angiogenesis after acute myocardial infarction through increasing ROS production and enhancing ER stress-mediated autophagy. J. Cell. Physiol. 234(10), 17690–17703 (2019).
    • 31. Hernandez-Resendiz S, Chinda K, Ong SB, Cabrera-Fuentes H, Zazueta C, Hausenloy DJ. The role of redox dysregulation in the inflammatory response to acute myocardial ischaemia-reperfusion injury – adding fuel to the fire. Curr. Med. Chem. 25(11), 1275–1293 (2018).
    • 32. Loguinova M, Pinegina N, Kogan V et al. Monocytes of different subsets in complexes with platelets in patients with myocardial infarction. Thromb. Haemost. 118(11), 1969–1981 (2018).
    • 33. Rainger GE, Chimen M, Harrison MJ et al. The role of platelets in the recruitment of leukocytes during vascular disease. Platelets 26(6), 507–520 (2015).
    • 34. Kim Y, Nurakhayev S, Nurkesh A, Zharkinbekov Z, Saparov A. Macrophage polarization in cardiac tissue repair following myocardial infarction. Int. J. Mol. Sci. 22(5), 2751 (2021).
    • 35. Peet C, Ivetic A, Bromage DI, Shah AM. Cardiac monocytes and macrophages after myocardial infarction. Cardiovasc. Res. 116(6), 1101–1112 (2020).
    • 36. Ibarra-Lara L, Sanchez-Aguilar M, Soria-Castro E et al. Clofibrate treatment decreases inflammation and reverses myocardial infarction-induced remodelation in a rodent experimental model. Molecules 24(2), 270 (2019).
    • 37. Clerc OF, Haaf P, Buechel RR, Gaemperli O, Zellweger MJ. New therapies to modulate post-infarction inflammatory alterations in the myocardium: state of the art and forthcoming applications. Curr. Radiopharm. 14(3), 273–299 (2021).
    • 38. Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ. Res. 110(1), 159–173 (2012).
    • 39. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356(6337), 513–519 (2017).
    • 40. Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-β signaling in cardiac remodeling. J. Mol. Cell. Cardiol. 51(4), 600–606 (2011).
    • 41. Chen W, Frangogiannis NG. Fibroblasts in post-infarction inflammation and cardiac repair. Biochim. Biophys. Acta 1833(4), 945–953 (2013).
    • 42. Yang Z, Wan J, Pan W, Zou J. Expression of vascular endothelial growth factor in cardiac repair: signaling mechanisms mediating vascular protective effects. Int. J. Biol. Macromol. 113, 179–185 (2018).
    • 43. Rong SL, Wang XL, Wang YC et al. Anti-inflammatory activities of hepatocyte growth factor in post-ischemic heart failure. Acta Pharmacol. Sin. 39(10), 1613–1621 (2018).
    • 44. Madonna R, Petrov L, Teberino MA et al. Transplantation of adipose tissue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes repair in murine myocardial infarction. Cardiovasc. Res. 108(1), 39–49 (2015).
    • 45. Bourron O, Le Bouc Y, Berard L et al. Impact of age-adjusted insulin-like growth factor 1 on major cardiovascular events after acute myocardial infarction: results from the FAST-MI registry. J. Clin. Endocrinol. Metab. 100(5), 1879–1886 (2015).
    • 46. Heinen A, Nederlof R, Panjwani P et al. IGF1 treatment improves cardiac remodeling after infarction by targeting myeloid cells. Mol. Ther. 27(1), 46–58 (2019).
    • 47. Lin M, Liu X, Zheng H et al. IGF-1 enhances BMSC viability, migration, and anti-apoptosis in myocardial infarction via secreted frizzled-related protein 2 pathway. Stem Cell Res. Ther. 11(1), 22 (2020).
    • 48. Zhang A, Hu J, Xu Z, Wang C, Bian L. TNF-alpha and IL-18 as diagnostic markers for acute myocardial infarction (AMI) and risk factors for AMI-related death. Int. J. Clin. Exp. Med. 13(8), 5941–5949 (2020).
    • 49. O'Brien LC, Mezzaroma E, Van Tassell BW et al. Interleukin-18 as a therapeutic target in acute myocardial infarction and heart failure. Mol. Med. 20, 221–229 (2014).
    • 50. Venkatachalam K, Prabhu SD, Reddy VS, Boylston WH, Valente AJ, Chandrasekar B. Neutralization of interleukin-18 ameliorates ischemia/reperfusion-induced myocardial injury. J. Biol. Chem. 284(12), 7853–7865 (2009).
    • 51. Gu H, Xie M, Xu L, Zheng X, Yang Y, Lv X. The protective role of interleukin-18 binding protein in a murine model of cardiac ischemia/reperfusion injury. Transpl. Int. 28(12), 1436–1444 (2015).
    • 52. Edlinger C, Wernly B, Leisch M et al. Analysis of ambient influences affecting interleukin-6 secretion in the context of clinical trials of stem cell therapy for myocardial infarction. Clin. Lab. 62(6), 1061–1068 (2016).
    • 53. Neri M, Fineschi V, Di Paolo M et al. Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction. Curr. Vasc. Pharmacol. 13(1), 26–36 (2015).
    • 54. Wilkowska A, Pikula M, Rynkiewicz A, Wdowczyk-Szulc J, Trzonkowski P, Landowski J. Increased plasma pro-inflammatory cytokine concentrations after myocardial infarction and the presence of depression during next 6-months. Psychiatr. Pol. 49(3), 455–464 (2015).
    • 55. Fanola CL, Morrow DA, Cannon CP et al. Interleukin-6 and the risk of adverse outcomes in patients after an acute coronary syndrome: observations from the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib–Thrombolysis in Myocardial Infarction 52) trial. J. Am. Heart Assoc. 6(10), e005637 (2017).
    • 56. Jong WMC, Ten Cate H, Linnenbank AC et al. Reduced acute myocardial ischemia–reperfusion injury in IL-6-deficient mice employing a closed-chest model. Inflamm. Res. 65(6), 489–499 (2016).
    • 57. Orrem HL, Nilsson PH, Pischke SE et al. IL-6 receptor inhibition by tocilizumab attenuated expression of C5a receptor 1 and 2 in non-ST-elevation myocardial infarction. Front. Immunol. 9, 2037 (2018).
    • 58. Shahrivari M, Wise E, Resende M et al. Peripheral blood cytokine levels after acute myocardial infarction IL-1β- and IL-6-related impairment of bone marrow function. Circ. Res. 120(12), 1947–1957 (2017).
    • 59. Cen W, Chen Z, Gu N, Hoppe R. Prevention of AMI induced ventricular remodeling: inhibitory effects of heart-protecting musk pill on IL-6 and TNF-alpha. Evid. Based Complement. Alternat. Med. 2017, 3217395 (2017).
    • 60. Jung M, Ma Y, Iyer RP et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res. Cardiol. 112(3), 33 (2017).
    • 61. Cihakova D. Interleukin-10 stiffens the heart. J. Exp. Med. 215(2), 379–381 (2018).
    • 62. Cambier L, De Couto G, Ibrahim A et al. RNA fragment in extracellular vesicles confers cardioprotection via modulation of IL-10 expression and secretion. EMBO Mol. Med. 9(3), 337–352 (2017).
    • 63. Meng D, Han S, Jeong IS, Kim SW. Interleukin 10-secreting MSCs via TALEN-mediated gene editing attenuates left ventricular remodeling after myocardial infarction. Cell. Physiol. Biochem. 52(4), 728–741 (2019).
    • 64. Pickup MW, Owens P, Moses HL. TGF-β, bone morphogenetic protein, and activin signaling and the tumor microenvironment. Cold Spring Harb. Perspect. Biol. 9(5), a022285 (2017).
    • 65. Lu Q, Wang WW, Zhang MZ et al. ROS induces epithelial-mesenchymal transition via the TGF-1/PI3K/Akt/mTOR pathway in diabetic nephropathy. Exp. Ther. Med. 17(1), 835–846 (2019).
    • 66. Zhang S, Che D, Yang F et al. Tumor-associated macrophages promote tumor metastasis via the TGF-β/SOX9 axis in non-small cell lung cancer. Oncotarget 8(59), 99801–99815 (2017).
    • 67. Frangogiannis NG. The role of transforming growth factor (TGF)-β in the infarcted myocardium. J. Thorac. Dis. 9, S52–S63 (2017).
    • 68. Goumans MJ, Ten Dijke P. TGF-β signaling in control of cardiovascular function. Cold Spring Harb. Perspect. Biol. 10(2), a022210 (2018).
    • 69. Zhang XG, Wei Y, Jiang J, Wang L, Liang HY, Lei CB. Effect of TGF-β1 on myocardial cell apoptosis in rats with acute myocardial infarction via MAPK signaling pathway. Eur. Rev. Med. Pharmacol. Sci. 24(3), 1350–1356 (2020).
    • 70. Dergilev KV, Tsokolaeva ZI, Beloglazova IB, Ratner EI, Parfenova EV. Transforming growth factor beta (TGF-β1) induces pro-reparative phenotypic changes in epicardial cells in mice. Bull. Exp. Biol. Med. 170(4), 565–570 (2021).
    • 71. Wu L, Chen G, Song J. Association between TGF-β1-913G/C polymorphism and myocardial infarction risk in a Chinese Han population: a case–control study. Biosci. Rep. 39, BSR20190315 (2019).
    • 72. Zhang Z, Long C, Guan Y, Song M. Hepatocyte growth factor intervention to reduce myocardial injury and improve cardiac function on diabetic myocardial infarction rats. Eur. J. Histochem. 64, 3124 (2020).
    • 73. Wang LS, Wang H, Zhang QL, Yang ZJ, Kong FX, Wu CT. Hepatocyte growth factor gene therapy for ischemic diseases. Hum. Gene Ther. 29(4), 413–423 (2018).
    • 74. Meng H, Bo C, Tao Z et al. Safety and efficacy of adenovirus carrying hepatocyte growth factor gene by percutaneous endocardial injection for treating post-infarct heart failure: a phase IIa clinical trial. Curr. Gene Ther. 18(2), 125–130 (2018).
    • 75. Gallo S, Sala V, Gatti S, Crepaldi T. Cellular and molecular mechanisms of HGF/Met in the cardiovascular system. Clin. Sci. 129(12), 1173–1193 (2015).
    • 76. Itoh N, Ohta H, Nakayama Y, Konishi M. Roles of FGF signals in heart development, health, and disease. Front. Cell Dev. Biol. 4, 110 (2016).
    • 77. Rao Z, Shen D, Chen J et al. Basic fibroblast growth factor attenuates injury in myocardial infarction by enhancing hypoxia-inducible factor-1 alpha accumulation. Front. Pharmacol. 11, 1193 (2020).
    • 78. Yamasaki S, Nabeshima K, Sotomaru Y et al. Long-term serial cultivation of mouse induced pluripotent stem cells in serum-free and feeder-free defined medium. Int. J. Dev. Biol. 57(9–10), 715–724 (2013).
    • 79. Singla DK, Singla RD, Abdelli LS, Glass C. Fibroblast growth factor-9 enhances M2 macrophage differentiation and attenuates adverse cardiac remodeling in the infarcted diabetic heart. PLoS One 10(3), e0120739 (2015).
    • 80. Ruperez C, Lerin C, Ferrer-Curriu G et al. Autophagic control of cardiac steatosis through FGF21 in obesity-associated cardiomyopathy. Int. J. Cardiol. 260, 163–170 (2018).
    • 81. Gomez-Samano MA, Grajales-Gomez M, Zuarth-Vazquez JM et al. Fibroblast growth factor 21 and its novel association with oxidative stress. Redox Biol. 11, 335–341 (2017).
    • 82. Yan X, Chen J, Zhang C et al. FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. J. Cell. Mol. Med. 19(7), 1557–1568 (2015).
    • 83. Pan X, Shao Y, Wu F et al. FGF21 prevents angiotensin II-induced hypertension and vascular dysfunction by activation of ACE2/angiotensin-(1–7) axis in mice. Cell Metab. 27(6), 1323–1337.e5 (2018).
    • 84. Bergmark BA, Udell JA, Morrow DA et al. Association of fibroblast growth factor 23 with recurrent cardiovascular events in patients after an acute coronary syndrome: a secondary analysis of a randomized clinical trial. JAMA Cardiol. 3(6), 473–480 (2018).
    • 85. Fuernau G, Poess J, Denks D et al. Fibroblast growth factor 23 in acute myocardial infarction complicated by cardiogenic shock: a biomarker substudy of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. Crit. Care 18(6), 713 (2014).
    • 86. Ziff OJ, Bromage DI, Yellon DM, Davidson SM. Therapeutic strategies utilizing SDF-1 alpha in ischaemic cardiomyopathy. Cardiovasc. Res. 114(3), 358–367 (2018).
    • 87. Gong XH, Liu H, Wang SJ, Liang SW, Wang GG. Exosomes derived from SDF1-overexpressing mesenchymal stem cells inhibit ischemic myocardial cell apoptosis and promote cardiac endothelial microvascular regeneration in mice with myocardial infarction. J. Cell. Physiol. 234(8), 13878–13893 (2019).
    • 88. Goldstone AB, Burnett CE, Cohen JE et al. SDF 1-alpha attenuates myocardial injury without altering the direct contribution of circulating cells. J. Cardiovasc. Transl. Res. 11(4), 274–284 (2018).
    • 89. Huang FY, Xia TL, Li JL et al. The bifunctional SDF-1-AnxA5 fusion protein protects cardiac function after myocardial infarction. J. Cell. Mol. Med. 23(11), 7673–7684 (2019).
    • 90. Su G, Liu L, Yang L, Mu Y, Guan L. Homing of endogenous bone marrow mesenchymal stem cells to rat infarcted myocardium via ultrasound-mediated recombinant SDF-1 alpha adenovirus in microbubbles. Oncotarget 9(1), 477–487 (2018).
    • 91. Chung ES, Miller L, Patel AN et al. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized phase II trial. Eur. Heart J. 36(33), 2228–2238 (2015).
    • 92. Cacciapuoti M, Johnson B, Kapdia A, Powell S, Gallicano GI. The role of neuregulin and stem cells as therapy post-myocardial infarction. Stem Cells Dev. 29(19), 1266–1274 (2020).
    • 93. Lin Y, Liu H, Wang X. Neuregulin-1, a microvascular endothelial-derived protein, protects against myocardial ischemia–reperfusion injury (review). Int. J. Mol. Med. 46(3), 925–935 (2020).
    • 94. Dugaucquier L, Feyen E, Mateiu L, Bruyns TAM, De Keulenaer GW, Segers VFM. The role of endothelial autocrine NRG1/ERBB4 signaling in cardiac remodeling. Am. J. Physiol. Heart Circ. Physiol. 319(2), H443–H455 (2020).
    • 95. Miao J, Huang S, Su YR et al. Effects of endogenous serum neuregulin-1 on morbidity and mortality in patients with heart failure and left ventricular systolic dysfunction. Biomarkers 23(7), 704–708 (2018).
    • 96. Ganapathy B, Nandhagopal N, Polizzotti BD et al. Neuregulin-1 administration protocols sufficient for stimulating cardiac regeneration in young mice do not induce somatic, organ, or neoplastic growth. PLoS One 11(5), e0155456 (2016).
    • 97. Yang G, Wu C, Li L et al. Neuregulin-1 protects cardiac electrical conduction through downregulating matrix metalloproteinase-9 and upregulating connexin 43 in a rat myocardial infarction model. Pharmazie 74(4), 231–234 (2019).
    • 98. Rao P, Liu Z, Duan H et al. Pretreatment with neuregulin-1 improves cardiac electrophysiological properties in a rat model of myocardial infarction. Exp. Ther. Med. 17(4), 3141–3149 (2019).
    • 99. Cohen JE, Goldstone AB, Wang H et al. A bioengineered neuregulin–hydrogel therapy reduces scar size and enhances post-infarct ventricular contractility in an ovine large animal model. J. Cardiovasc. Dev. Dis. 7(4), 53 (2020).
    • 100. Epstein SE, Kornowski R, Fuchs S, Dvorak HF. Angiogenesis therapy – amidst the hype, the neglected potential for serious side effects. Circulation 104(1), 115–119 (2001).
    • 101. Inoue M, Itoh H, Ueda M et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions – possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 98(20), 2108–2116 (1998).
    • 102. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium – deleterious effects of unregulated expression. Circulation 102(8), 898–901 (2000).
    • 103. Liu G, Li L, Huo D et al. A VEGF delivery system targeting MI improves angiogenesis and cardiac function based on the tropism of MSCs and layer-by-layer self-assembly. Biomaterials 127, 117–131 (2017).
    • 104. Scott RC, Rosano JM, Ivanov Z et al. Targeting VEGF-encapsulated immunoliposomes to MI heart improves vascularity and cardiac function. FASEB J. 23(10), 3361–3367 (2009).
    • 105. Awada HK, Hwang MTP, Wang YD. Towards comprehensive cardiac repair and regeneration after myocardial infarction: aspects to consider and proteins to deliver. Biomaterials 82, 94–112 (2016).
    • 106. Fan C, Shi J, Zhuang Y et al. Myocardial-infarction-responsive smart hydrogels targeting matrix metalloproteinase for on-demand growth factor delivery. Adv. Mater. 31(40), e1902900 (2019). •• Developed a dual-functional AMI-responsive GST-TIMP-bFGF/collagen–glutathione hydrogel capable of on-demand drug delivery.
    • 107. Atienza-Roca P, Kieser DC, Cui X et al. Visible light mediated PVA–tyramine hydrogels for covalent incorporation and tailorable release of functional growth factors. Biomater. Sci. 8(18), 5005–5019 (2020).
    • 108. Yuan Z, Tsou YH, Zhang XQ et al. Injectable citrate-based hydrogel as an angiogenic biomaterial improves cardiac repair after myocardial infarction. ACS Appl. Mater. Interfaces 11(42), 38429–38439 (2019).
    • 109. Feng J, Wu Y, Chen W et al. Sustained release of bioactive IGF-1 from a silk fibroin microsphere-based injectable alginate hydrogel for the treatment of myocardial infarction. J. Mater. Chem. B 8(2), 308–315 (2020). •• Developed a composite hydrogel that may represent a powerful platform in cardiac tissue engineering to treat myocardial infarction and lead to myocardial repair and tissue reconstruction.
    • 110. Saludas L, Pascual-Gil S, Roli F, Garbayo E, Blanco-Prieto MJ. Heart tissue repair and cardioprotection using drug delivery systems. Maturitas 110, 1–9 (2018).
    • 111. Qi Q, Lu L, Li HQ et al. Spatiotemporal delivery of nanoformulated liraglutide for cardiac regeneration after myocardial infarction. Int. J. Nanomedicine 12, 4835–4848 (2017).
    • 112. Formiga FR, Pelacho B, Garbayo E et al. Sustained release of VEGF through PLGA microparticles improves vasculogenesis and tissue remodeling in an acute myocardial ischemia–reperfusion model. J. Control. Release 147(1), 30–37 (2010).
    • 113. Chang MY, Yang YJ, Chang CH et al. Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. J. Control. Rel. 170(2), 287–294 (2013).
    • 114. Davis ME, Hsieh PCH, Takahashi T et al. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc. Natl Acad. Sci. U. S. A. 103(21), 8155–8160 (2006).
    • 115. Hsieh PCH, 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. 116(1), 237–248 (2006).
    • 116. Kim JH, Jung Y, Kim SH et al. The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides. Biomaterials 32(26), 6080–6088 (2011).
    • 117. Yin R, Yang D, Wu H, Huang K, Wu X, Chen Y. Intramyocardial injection of vascular endothelial growth factor gene improves cardiac performance and inhibits cardiomyocyte apoptosis. Eur. J. Heart Fail. 9(4), 343–351 (2007).
    • 118. Wu X, Wang D, Qin K et al. Cardiac repair with echocardiography-guided multiple percutaneous left ventricular intramyocardial injection of hiPSC-CMs after myocardial infarction. Front. Cardiovasc. Med. 8, 768873 (2021).
    • 119. Maslov M, Foianini S, Lovich M. Delivery of drugs, growth factors, genes and stem cells via intrapericardial, epicardial and intramyocardial routes for sustained local targeted therapy of myocardial disease. Expert Opin. Drug Deliv. 14(10), 1227–1239 (2017). • Provides an historical overview of six decades of evolution in local myocardial delivery.
    • 120. Mei X, Cheng K. Recent development in therapeutic cardiac patches. Front. Cardiovasc. Med. 7, 610364 (2020).
    • 121. Yang SY, O'Cearbhaill ED, Sisk GC et al. A bio-inspired swellable microneedle adhesive for mechanical interlocking with tissue. Nat. Commun. 4, 1702 (2013).
    • 122. Lakshmanan R, Kumaraswamy P, Krishnan UM, Sethuraman S. Engineering a growth factor embedded nanofiber matrix niche to promote vascularization for functional cardiac regeneration. Biomaterials 97, 176–195 (2016). • Confirms the effectiveness of growth factor-embedded nanofiber matrix in the restoration of cardiac function after ischemia compared with conventional patch material.
    • 123. Park BW, Jung SH, Das S et al. In vivo priming of human mesenchymal stem cells with hepatocyte growth factor-engineered mesenchymal stem cells promotes therapeutic potential for cardiac repair. Sci. Adv. 6(13), eaay6994 (2020). • Developed a strategy for in vivo priming in which bone marrow-derived mesenchymal stromal cells (BM-MSCs) are primed in vivo in myocardial infarction-induced hearts through genetically engineered HGF-expressing MSCs.
    • 124. Shi H, Xue T, Yang Y et al. Microneedle-mediated gene delivery for the treatment of ischemic myocardial disease. Sci. Adv. 6(25), eaaz3621 (2020). •• Developed a promising tool with great versatility for the delivery of various agents to treat ischemic myocardial disease.
    • 125. Tang J, Wang J, Huang K et al. Cardiac cell-integrated microneedle patch for treating myocardial infarction. Sci. Adv. 4(11), eaat9365 (2018).
    • 126. Bar A, Cohen S. Inducing endogenous cardiac regeneration: can biomaterials connect the dots? Front. Bioeng. Biotechnol. 8, 126 (2020).
    • 127. Edelman ER, Nugent MA, Karnovsky MJ. Perivascular and intravenous administration of basic fibroblast growth factor: vascular and solid organ deposition. Proc. Natl Acad. Sci. USA 90(4), 1513–1517 (1993).
    • 128. Qiao B, Nie JJ, Shao Y et al. Functional nanocomplexes with vascular endothelial growth factor A/C isoforms improve collateral circulation and cardiac function. Small 16(4), e1905925 (2020).
    • 129. Kim H, Yun N, Mun D et al. Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes. Biochem. Biophys. Res. Commun. 499(4), 803–808 (2018).
    • 130. Su T, Huang K, Ma H et al. Platelet-inspired nanocells for targeted heart repair after ischemia/reperfusion injury. Adv. Funct. Mater. 29(4), 1803567 (2019).
    • 131. Tang J, Cui X, Zhang Z et al. Injection-free delivery of MSC-derived extracellular vesicles for myocardial infarction therapeutics. Adv. Healthc. Mater. 11(5), e2100312 (2022). •• Developed a novel approach using a spray technique that helps achieve minimally invasive.
    • 132. Mori D, Miyagawa S, Yajima S et al. Cell spray transplantation of adipose-derived mesenchymal stem cell recovers ischemic cardiomyopathy in a porcine model. Transplantation 102(12), 2012–2024 (2018).
    • 133. Miragoli M, Ceriotti P, Iafisco M et al. Inhalation of peptide-loaded nanoparticles improves heart failure. Sci. Transl. Med. 10(424), eaan6205 (2018).
    • 134. Richards DJ, Li Y, Kerr CM et al. Human cardiac organoids for the modelling of myocardial infarction and drug cardiotoxicity. Nat. Biomed. Eng. 4(4), 446–462 (2020).
    • 135. Yang X, Zhang Y, Hosaka K et al. VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients. Proc. Natl Acad. Sci. U. S. A. 112(22), e2900–e2909 (2015).
    • 136. Hao H, Ma S, Zheng C et al. Excessive fibroblast growth factor 23 promotes renal fibrosis in mice with type 2 cardiorenal syndrome. Aging (Albany NY) 13(2), 2982–3009 (2021).
    • 137. Kim YS, Lee HJ, Han MH, Yoon NK, Kim YC, Ahn J. Effective production of human growth factors in Escherichia coli by fusing with small protein 6HFh8. Microb. Cell Fact. 20(1), 9 (2021).