245
Views
0
CrossRef citations to date
0
Altmetric
Review

TGF-β as a therapeutic target in the infarcted and failing heart: cellular mechanisms, challenges, and opportunities

Pages 45-56 | Received 20 Oct 2023, Accepted 06 Feb 2024, Published online: 19 Feb 2024

References

  • Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (Esc)developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200. doi: 10.1093/eurheartj/ehw128
  • Schwinger RHG. Pathophysiology of heart failure. Cardiovasc Diagn Ther. 2021;11(1):263–76. doi: 10.21037/cdt-20-302
  • Savarese G, Stolfo D, Sinagra G, et al. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol. 2022;19(2):100–16. doi: 10.1038/s41569-021-00605-5
  • Frangogiannis NG. Cardiac fibrosis. Cardiovasc Res. 2021;117(6):1450–88. doi: 10.1093/cvr/cvaa324
  • Frangogiannis NG. Transforming growth factor–β in tissue fibrosis. J Exp Med. 2020;217(3):e20190103. doi: 10.1084/jem
  • Lodyga M, Hinz B. TGF-beta1 - a truly transforming growth factor in fibrosis and immunity. Semin Cell Dev Biol. 2020;101:123–139. doi: 10.1016/j.semcdb.2019.12.010
  • Massague J, Sheppard D. TGF-β signaling in health and disease. Cell. 2023;186(19):4007–4037. doi: 10.1016/j.cell.2023.07.036
  • Koitabashi N, Danner T, Zaiman AL, et al. Pivotal role of cardiomyocyte TGF-β signaling in the murine pathological response to sustained pressure overload. J Clin Invest. 2011;121(6):2301–2312. doi: 10.1172/JCI44824
  • Chen B, Huang S, Su Y, et al. Macrophage Smad3 protects the infarcted heart, stimulating phagocytosis and regulating inflammation. Circ Res. 2019;125(1):55–70. doi: 10.1161/CIRCRESAHA.119.315069
  • Goumans MJ, Ten Dijke P. TGF-β Signaling in Control of Cardiovascular Function. Cold Spring Harb Perspect Biol. 2018;10(2):10. doi: 10.1101/cshperspect.a022210
  • Hinck AP, Mueller TD, Springer TA. Structural biology and evolution of the TGF-β family. Cold Spring Harb Perspect Biol. 2016;8(12):a022103. doi: 10.1101/cshperspect.a022103
  • Lyons RM, Keski-Oja J, Moses HL. Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Bio. 1988;106(5):1659–65. doi: 10.1083/jcb.106.5.1659
  • Khalil N, Corne S, Whitman C, et al. Plasmin regulates the activation of cell-associated latent TGF-beta 1 secreted by rat alveolar macrophages after in vivo bleomycin injury. Am J Respir Cell Mol Biol. 1996;15(2):252–9. doi: 10.1165/ajrcmb.15.2.8703482
  • Guo M, Mathieu PA, Linebaugh B, et al. Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-β. J Biol Chem. 2002;277(17):14829–14837. doi: 10.1074/jbc.M108180200
  • Yao Y, Hu C, Song Q, et al. ADAMTS16 activates latent TGF-β, accentuating fibrosis and dysfunction of the pressure-overloaded heart. Cardiovasc Res. 2019;116(5):956–969. doi: 10.1093/cvr/cvz187
  • Munger JS, Huang X, Kawakatsu H, et al. A mechanism for regulating pulmonary inflammation and fibrosis: the Integrin αvβ6 binds and activates latent TGF β1. Cell. 1999;96(3):319–328. doi: 10.1016/S0092-8674(00)80545-0
  • Hakkinen L, Koivisto L, Gardner H, et al. Increased expression of β6-integrin in skin leads to spontaneous development of chronic wounds. Am J Pathol. 2004;164(1):229–242. doi: 10.1016/S0002-9440(10)63113-6
  • Sarrazy V, Koehler A, Chow ML, et al. Integrins αvβ5 and αvβ3 promote latent TGF-β1 activation by human cardiac fibroblast contraction. Cardiovasc Res. 2014;102(3):407–417. doi: 10.1093/cvr/cvu053
  • Klingberg F, Chau G, Walraven M, et al. The fibronectin ED-A domain enhances recruitment of latent TGF-beta-binding protein-1 to the fibroblast matrix. J Cell Sci. 2018:131. doi: 10.1242/jcs.201293
  • Serini G, Bochaton-Piallat ML, Ropraz P, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-β1. J Cell Bio. 1998;142(3):873–881. doi: 10.1083/jcb.142.3.873
  • Robertson IB, Rifkin DB. Regulation of the bioavailability of TGF-β and TGF-β-related proteins. Cold Spring Harb Perspect Biol. 2016;8(6):a021907. doi: 10.1101/cshperspect.a021907
  • Massague J. How cells read TGF-β signals. Nat Rev Mol Cell Biol. 2000;1(3):169–178. doi: 10.1038/35043051
  • Heldin CH, Moustakas A. Signaling receptors for TGF-β family members. Cold Spring Harb Perspect Biol. 2016;8(8):a022053. doi: 10.1101/cshperspect.a022053
  • Goumans MJ, Valdimarsdottir G, Itoh S, et al. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002;21(7):1743–1753. doi: 10.1093/emboj/21.7.1743
  • Oh SP, Seki T, Goss KA, et al. Activin receptor-like kinase 1 modulates transforming growth factor-β1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000;97(6):2626–2631. doi: 10.1073/pnas.97.6.2626
  • Goumans MJ, Valdimarsdottir G, Itoh S, et al. Activin Receptor-like Kinase (ALK)1 is an antagonistic mediator of lateral TGFβ/ALK5 signaling. Mol Cell. 2003;12(4):817–828. doi: 10.1016/S1097-2765(03)00386-1
  • Nurgazieva D, Mickley A, Moganti K, et al. TGF-β1, but not bone morphogenetic proteins, activates Smad1/5 pathway in primary human macrophages and induces expression of proatherogenic genes. J Immunol. 2015;194(2):709–718. doi: 10.4049/jimmunol.1300272
  • Zhang H, Du L, Zhong Y, et al. Transforming growth factor-β stimulates Smad1/5 signaling in pulmonary artery smooth muscle cells and fibroblasts of the newborn mouse through ALK1. Am J Physiol Lung Cell Mol Physiol. 2017;313(3):L615–L27. doi: 10.1152/ajplung.00079.2017
  • Feng XH, Derynck R. SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS. Annu Rev Cell Dev Biol. 2005;21(1):659–693. doi: 10.1146/annurev.cellbio.21.022404.142018
  • Imamura T, Takase M, Nishihara A, et al. Smad6 inhibits signalling by the TGF-β superfamily. Nature. 1997;389(6651):622–626. doi: 10.1038/39355
  • Nakao A, Afrakhte M, Moren A, et al. Identification of Smad7, a TGFβ-inducible antagonist of TGF-β signalling. Nature. 1997;389(6651):631–635. doi: 10.1038/39369
  • Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol. 2016;8(5):8. doi: 10.1101/cshperspect.a021873
  • Humeres C, Shinde AV, Hanna A, et al. Smad7 effects on TGF-β and ErbB2 restrain myofibroblast activation and protect from postinfarction heart failure. J Clin Investigation. 2022;132(3):e146926. doi: 10.1172/JCI
  • Funaba M, Zimmerman CM, Mathews LS. Modulation of Smad2-mediated signaling by extracellular signal-regulated kinase. J Biol Chem. 2002;277(44):41361–8. doi: 10.1074/jbc.M204597200
  • Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev. 1999;13(7):804–16. doi: 10.1101/gad.13.7.804
  • Furukawa F, Matsuzaki K, Mori S, et al. p38 MAPK mediates fibrogenic signal through Smad3 phosphorylation in rat myofibroblasts. Hepatology. 2003;38(4):879–89. doi: 10.1002/hep.1840380414
  • Yoshida K, Matsuzaki K, Mori S, et al. Transforming growth factor-β and platelet-derived growth factor signal via c-jun N-Terminal kinase-dependent Smad2/3 phosphorylation in rat hepatic stellate cells after acute liver injury. Am J Pathol. 2005;166(4):1029–1039. doi: 10.1016/S0002-9440(10)62324-3
  • Seay U, Sedding D, Krick S, et al. Transforming growth factor-β-dependent growth inhibition in primary vascular smooth muscle cells is p38-dependent. J Pharmacol Exp Ther. 2005;315(3):1005–1012. doi: 10.1124/jpet.105.091249
  • Schwartze JT, Becker S, Sakkas E, et al. Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts. J Biol Chem. 2014;289(6):3262–3275. doi: 10.1074/jbc.M113.541052
  • Lebrin F, Goumans MJ, Jonker L, et al. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO J. 2004;23(20):4018–4028. doi: 10.1038/sj.emboj.7600386
  • Duncan MR, Frazier KS, Abramson S, et al. Connective tissue growth factor mediates transforming growth factor β-induced collagen synthesis: down-regulation by cAMP. FASEB J. 1999;13(13):1774–1786. doi: 10.1096/fasebj.13.13.1774
  • Abreu JG, Ketpura NI, Reversade B, et al. Connective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-β. Nat Cell Biol. 2002;4(8):599–604. doi: 10.1038/ncb826
  • Mori T, Kawara S, Shinozaki M, et al. Role and interaction of connective tissue growth factor with transforming growth factor-? in persistent fibrosis: a mouse fibrosis model. J Cell Physiol. 1999;181(1):153–159. doi: 10.1002/(SICI)1097-4652(199910)181:1<153:AID-JCP16>3.0.CO;2-K
  • Schafer S, Viswanathan S, Widjaja AA, et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature. 2017;552(7683):110–5. doi: 10.1038/nature24676
  • Wahl SM, Allen JB, Weeks BS, et al. Transforming growth factor beta enhances integrin expression and type IV collagenase secretion in human monocytes. Proc Natl Acad Sci U S A. 1993;90(10):4577–81. doi: 10.1073/pnas.90.10.4577
  • Wahl SM, Hunt DA, Wakefield LM, et al. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987;84(16):5788–92. doi: 10.1073/pnas.84.16.5788
  • Basoni C, Nobles M, Grimshaw A, et al. Inhibitory control of TGF-β1 on the activation of Rap1, CD11b, and transendothelial migration of leukocytes. FASEB J. 2005;19(7):822–824. doi: 10.1096/fj.04-3085fje
  • Kitamura M, Suto T, Yokoo T, et al. Transforming growth factor-beta 1 is the predominant paracrine inhibitor of macrophage cytokine synthesis produced by glomerular mesangial cells. J Immunol. 1996;156(8):2964–71. doi: 10.4049/jimmunol.156.8.2964
  • Fantini MC, Becker C, Monteleone G, et al. Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004;172(9):5149–5153. doi: 10.4049/jimmunol.172.9.5149
  • Deten A, Holzl A, Leicht M, et al. Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats. J Mol Cell Cardiol. 2001;33(6):1191–207. doi: 10.1006/jmcc.2001.1383
  • Dewald O, Ren G, Duerr GD, et al. Of mice and dogs: species-specific differences in the inflammatory response following myocardial infarction. Am J Pathol. 2004;164(2):665–77. doi: 10.1016/S0002-9440(10)63154-9
  • Xia Y, Lee K, Li N, et al. Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload. Histochem Cell Biol. 2009;131(4):471–81. doi: 10.1007/s00418-008-0541-5
  • Takahashi N, Calderone A, Izzo NJ Jr., et al. Hypertrophic stimuli induce transforming growth factor-beta 1 expression in rat ventricular myocytes. J Clin Invest. 1994;94(4):1470–6. doi: 10.1172/JCI117485
  • Reddy S, Zhao M, Hu DQ, et al. Physiologic and molecular characterization of a murine model of right ventricular volume overload. Am J Physiol Heart Circ Physiol. 2013;304(10):H1314–27. doi: 10.1152/ajpheart.00776.2012
  • Teekakirikul P, Eminaga S, Toka O, et al. Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires tgf-β. J Clin Invest. 2010;120(10):3520–3529. doi: 10.1172/JCI42028
  • Bhandary B, Meng Q, James J, et al. Cardiac Fibrosis in Proteotoxic Cardiac Disease is Dependent Upon Myofibroblast TGF-β Signaling. J Am Heart Assoc. 2018;7(20):e010013. doi: 10.1161/JAHA.118.010013
  • Kania G, Blyszczuk P, Stein S, et al. Heart-infiltrating prominin-1 + /CD133 + progenitor cells represent the cellular source of transforming growth factor β–mediated cardiac fibrosis in experimental autoimmune myocarditis. Circ Res. 2009;105(5):462–470. doi: 10.1161/CIRCRESAHA.109.196287
  • Biernacka A, Cavalera M, Wang J, et al. Smad3 signaling promotes fibrosis while preserving cardiac and aortic geometry in obese diabetic mice. Circ Heart Fail. 2015;8(4):788–98. doi: 10.1161/CIRCHEARTFAILURE.114.001963
  • Pauschinger M, Knopf D, Petschauer S, et al. Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation. 1999;99(21):2750–6. doi: 10.1161/01.CIR.99.21.2750
  • Felkin LE, Lara-Pezzi E, George R, et al. Expression of extracellular matrix genes during myocardial recovery from heart failure after left ventricular assist device support. J Heart Lung Transplant. 2009;28(2):117–122. doi: 10.1016/j.healun.2008.11.910
  • Khan S, Joyce J, Margulies KB, et al. Enhanced bioactive myocardial transforming growth factor-β in advanced human heart failure. Circ J. 2014;78(11):2711–2718. doi: 10.1253/circj.CJ-14-0511
  • Li RK, Li G, Mickle DA, et al. Overexpression of transforming growth factor-β1 and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation. 1997;96(3):874–881. doi: 10.1161/01.CIR.96.3.874
  • Nagaraju CK, Robinson EL, Abdesselem M, et al. Myofibroblast phenotype and reversibility of fibrosis in patients with end-stage heart failure. J Am Coll Cardiol. 2019;73(18):2267–82. doi: 10.1016/j.jacc.2019.02.049
  • Bielecka-Dabrowa A, Sakowicz A, Misztal M, et al. Differences in biochemical and genetic biomarkers in patients with heart failure of various etiologies. Int J Cardiol. 2016;221:1073–80. doi: 10.1016/j.ijcard.2016.07.150
  • Tomita H, Egashira K, Ohara Y, et al. Early induction of transforming growth factor-β via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension. 1998;32(2):273–279. doi: 10.1161/01.HYP.32.2.273
  • Dewald O, Zymek P, Winkelmann K, et al. CCL2/Monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res. 2005;96(8):881–9. doi: 10.1161/01.RES.0000163017.13772.3a
  • Abe M, Oda N, Sato Y. Cell-associated activation of latent transforming growth factor-β by calpain. J Cell Physiol. 1998;174(2):186–193. doi: 10.1002/(SICI)1097-4652(199802)174:2<186:AID-JCP6>3.0.CO;2-K
  • Maeda S, Dean DD, Gomez R, et al. The first stage of transforming growth factor β1 activation is release of the large latent complex from the extracellular matrix of growth plate chondrocytes by matrix vesicle stromelysin-1 (MMP-3). Calcif Tissue Int. 2002;70(1):54–65. doi: 10.1007/s002230010032
  • Bourd-Boittin K, Bonnier D, Leyme A, et al. Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta. Hepatology. 2011;54(6):2173–84. doi: 10.1002/hep.24598
  • Frangogiannis NG, Ren G, Dewald O, et al. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Circulation. 2005;111(22):2935–2942. doi: 10.1161/CIRCULATIONAHA.104.510354
  • Xia Y, Dobaczewski M, Gonzalez-Quesada C, et al. Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. Hypertension. 2011;58(5):902–11. doi: 10.1161/HYPERTENSIONAHA.111.175323
  • Gonzalez-Quesada C, Cavalera M, Biernacka A, et al. Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation. Circ Res. 2013;113(12):1331–44. doi: 10.1161/CIRCRESAHA.113.302593
  • Schultz-Cherry S, Ribeiro S, Gentry L, et al. Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system. J Biol Chem. 1994;269(43):26775–82. doi: 10.1016/S0021-9258(18)47086-X
  • Ribeiro SM, Poczatek M, Schultz-Cherry S, et al. The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-β. J Biol Chem. 1999;274(19):13586–13593. doi: 10.1074/jbc.274.19.13586
  • Cucoranu I, Clempus R, Dikalova A, et al. NAD(P)H oxidase 4 mediates transforming growth factor-β1–Induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005;97(9):900–907. doi: 10.1161/01.RES.0000187457.24338.3D
  • Desmouliere A, Geinoz A, Gabbiani F, et al. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Bio. 1993;122(1):103–11. doi: 10.1083/jcb.122.1.103
  • Pearson CA, Pearson D, Shibahara S, et al. Tenascin: cDNA cloning and induction by TGF-beta. EMBO J. 1988;7(10):2977–82. doi: 10.1002/j.1460-2075.1988.tb03160.x
  • Horiuchi K, Amizuka N, Takeshita S, et al. Identification and characterization of a novel protein, periostin, with restricted expression to periosteum and periodontal ligament and increased expression by transforming growth factor β. J Bone Miner Res. 1999;14(7):1239–1249. doi: 10.1359/jbmr.1999.14.7.1239
  • Chen MM, Lam A, Abraham JA, et al. CTGF expression is induced by TGF- β in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis. J Mol Cell Cardiol. 2000;32(10):1805–1819. doi: 10.1006/jmcc.2000.1215
  • Eghbali M, Tomek R, Sukhatme VP, et al. Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts. Regulation of fibrillar collagen mRnas and expression of early transcription factors. Circ Res. 1991;69(2):483–90. doi: 10.1161/01.RES.69.2.483
  • Dobaczewski M, Bujak M, Li N, et al. Smad3 signaling critically regulates fibroblast phenotype and function in healing myocardial infarction. Circ Res. 2010;107(3):418–28. doi: 10.1161/CIRCRESAHA.109.216101
  • Chua CC, Chua BH, Zhao ZY, et al. Effect of growth factors on collagen metabolism in cultured human heart fibroblasts. Connect Tissue Res. 1991;26(4):271–281. doi: 10.3109/03008209109152444
  • Bujak M, Ren G, Kweon HJ, et al. Essential role of Smad3 in Infarct healing and in the pathogenesis of cardiac remodeling. Circulation. 2007;116(19):2127–38. doi: 10.1161/CIRCULATIONAHA.107.704197
  • Kong P, Shinde AV, Su Y, et al. Opposing actions of fibroblast and cardiomyocyte Smad3 signaling in the infarcted myocardium. Circulation. 2018;137(7):707–24. doi: 10.1161/CIRCULATIONAHA.117.029622
  • Russo I, Cavalera M, Huang S, et al. Protective effects of activated myofibroblasts in the pressure-overloaded myocardium are mediated through smad-dependent activation of a matrix-preserving program. Circ Res. 2019;124(8):1214–27. doi: 10.1161/CIRCRESAHA.118.314438
  • Huang S, Chen B, Su Y, et al. Distinct roles of myofibroblast-specific Smad2 and Smad3 signaling in repair and remodeling of the infarcted heart. J Mol Cell Cardiol. 2019;132:84–97. doi: 10.1016/j.yjmcc.2019.05.006
  • Ikeuchi M, Tsutsui H, Shiomi T, et al. Inhibition of TGF-beta signaling exacerbates early cardiac dysfunction but prevents late remodeling after infarction. Cardiovasc Res. 2004;64(3):526–535. doi: 10.1016/j.cardiores.2004.07.017
  • Okada H, Takemura G, Kosai K, et al. Postinfarction gene therapy against transforming growth factor-β signal modulates infarct tissue dynamics and attenuates left ventricular remodeling and heart failure. Circulation. 2005;111(19):2430–2437. doi: 10.1161/01.CIR.0000165066.71481.8E
  • Baxter GF, Mocanu MM, Brar BK, et al. Cardioprotective effects of transforming growth factor-β1 during early reoxygenation or reperfusion are mediated by p42/p44 MAPK. J Cardiovasc Pharmacol. 2001;38(6):930–939. doi: 10.1097/00005344-200112000-00015
  • Rainer PP, Hao S, Vanhoutte D, et al. Cardiomyocyte-specific transforming growth factor β suppression blocks neutrophil infiltration, augments multiple cytoprotective cascades, and reduces early mortality after myocardial infarction. Circ Res. 2014;114(8):1246–1257. doi: 10.1161/CIRCRESAHA.114.302653
  • Chen W. TGF-β regulation of T cells. Annu Rev Immunol. 2023;41(1):483–512. doi: 10.1146/annurev-immunol-101921-045939
  • Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014;32(1):51–82. doi: 10.1146/annurev-immunol-032713-120257
  • Chen B, Li R, Hernandez SC, et al. Differential effects of Smad2 and Smad3 in regulation of macrophage phenotype and function in the infarcted myocardium. J Mol Cell Cardiol. 2022;171:1–15. doi: 10.1016/j.yjmcc.2022.06.009
  • Weirather J, Hofmann UD, Beyersdorf N, et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res. 2014;115(1):55–67. doi: 10.1161/CIRCRESAHA.115.303895
  • Saxena A, Dobaczewski M, Rai V, et al. Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am J Physiol Heart Circ Physiol. 2014;307(8):H1233–42. doi: 10.1152/ajpheart.00328.2014
  • Blanton RM, Carrillo-Salinas FJ, Alcaide P. T-cell recruitment to the heart: friendly guests or unwelcome visitors? Am J Physiol Heart Circ Physiol. 2019;317(1):H124–H40. doi: 10.1152/ajpheart.00028.2019
  • Pepper MS. Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev. 1997;8(1):21–43. doi: 10.1016/S1359-6101(96)00048-2
  • Zhang Y, Yang X. The Roles of TGF-beta Signaling in Cerebrovascular Diseases. Front Cell Dev Biol. 2020;8:567682. doi: 10.3389/fcell.2020.567682
  • Pardali E, ten Dijke P. Transforming growth factor-beta signaling and tumor angiogenesis. Front Biosci (Landmark Ed). 2009;14(1):4848–4861. doi: 10.2741/3573
  • Walshe TE, Dole VS, Maharaj AS, et al. Inhibition of VEGF or TGF-β signaling activates endothelium and increases leukocyte rolling. Arterioscler Thromb Vasc Biol. 2009;29(8):1185–1192. doi: 10.1161/ATVBAHA.109.186742
  • Frangogiannis NG, Mendoza LH, Lewallen M, et al. Induction and suppression of interferon-inducible protein 10 in reperfused myocardial infarcts may regulate angiogenesis. FASEB J. 2001;15(8):1428–1430. doi: 10.1096/fj.00-0745fje
  • Chen S, Crawford M, Day RM, et al. RhoA modulates smad signaling during transforming growth factor-β-induced smooth muscle differentiation. J Biol Chem. 2006;281(3):1765–1770. doi: 10.1074/jbc.M507771200
  • Mao X, Debenedittis P, Sun Y, et al. Vascular smooth muscle cell Smad4 gene is important for mouse vascular development. Arterioscler Thromb Vasc Biol. 2012;32(9):2171–7. doi: 10.1161/ATVBAHA.112.253872
  • Rolle IG, Crivellari I, Zanello A, et al. Heart failure impairs the mechanotransduction properties of human cardiac pericytes. J Mol Cell Cardiol. 2021;151:15–30. doi: 10.1016/j.yjmcc.2020.10.016
  • Ren G, Michael LH, Entman ML, et al. Morphological characteristics of the microvasculature in healing myocardial infarcts. J Histochem Cytochem. 2002;50(1):71–9. doi: 10.1177/002215540205000108
  • Dobaczewski M, Akrivakis S, Nasser K, et al. Vascular mural cells in healing canine myocardial infarcts. J Histochem Cytochem. 2004;52(8):1019–29. doi: 10.1369/jhc.3A6210.2004
  • Alex L, Frangogiannis NG. Pericytes in the infarcted heart. Vasc Biol. 2019;1(1):H23–H31. doi: 10.1530/VB-19-0007
  • Zymek P, Bujak M, Chatila K, et al. The role of platelet-derived growth factor signaling in healing myocardial infarcts. J Am Coll Cardiol. 2006;48(11):2315–23. doi: 10.1016/j.jacc.2006.07.060
  • Quijada P, Park S, Zhao P, et al. Cardiac pericytes mediate the remodeling response to myocardial infarction. J Clin Invest. 2023;133(10). doi: 10.1172/JCI162188
  • Alex L, Tuleta I, Hernandez SC, et al. Cardiac Pericytes Acquire a Fibrogenic Phenotype and Contribute to Vascular Maturation After Myocardial Infarction. Circulation. 2023;148(11):882–98. doi: 10.1161/CIRCULATIONAHA.123.064155
  • Huynh LK, Hipolito CJ, Ten Dijke P. A perspective on the development of TGF-β inhibitors for cancer treatment. Biomolecules. 2019;9(11):743. doi: 10.3390/biom9110743
  • Akhurst RJ. Targeting TGF-β signaling for therapeutic gain. Cold Spring Harb Perspect Biol. 2017;9(10):a022301.
  • Lachapelle P, Li M, Douglass J, et al. Safer approaches to therapeutic modulation of TGF-beta signaling for respiratory disease. Pharmacol Ther. 2018;187:98–113. doi: 10.1016/j.pharmthera.2018.02.010
  • Anderton MJ, Mellor HR, Bell A, et al. Induction of heart valve lesions by small-molecule ALK5 inhibitors. Toxicol Pathol. 2011;39(6):916–24. doi: 10.1177/0192623311416259
  • Stauber AJ, Credille KM, Truex LL, et al. Nonclinical safety evaluation of a transforming growth factor beta receptor I kinase inhibitor in Fischer 344 rats and beagle dogs. J Clin Pract. 2014;4(3). doi: 10.4172/2161-0495.196
  • Morris JC, Tan AR, Olencki TE, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One. 2014;9(3):e90353. doi: 10.1371/journal.pone.0090353
  • Kovacs RJ, Maldonado G, Azaro A, et al. Cardiac safety of TGF-β receptor I kinase inhibitor LY2157299 monohydrate in cancer patients in a first-in-human dose study. Cardiovasc Toxicol. 2015;15(4):309–323. doi: 10.1007/s12012-014-9297-4
  • Kosmidou I, Redfors B, Selker HP, et al. Infarct size, left ventricular function, and prognosis in women compared to men after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction: results from an individual patient-level pooled analysis of 10 randomized trials. Eur Heart J. 2017;38(21):1656–63. doi: 10.1093/eurheartj/ehx159
  • Traub J, Schurmann P, Schmitt D, et al. Features of metabolic syndrome and inflammation independently affect left ventricular function early after first myocardial infarction. Int J Cardiol. 2023;370:43–50. doi: 10.1016/j.ijcard.2022.10.142
  • Uusimaa P, Risteli J, Niemela M, et al. Collagen scar formation after acute myocardial infarction: relationships to infarct size, left ventricular function, and coronary artery patency. Circulation. 1997;96(8):2565–72. doi: 10.1161/01.CIR.96.8.2565
  • Frantz S, Hu K, Adamek A, et al. Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction. Basic Res Cardiol. 2008;103(5):485–92. doi: 10.1007/s00395-008-0739-7
  • Frangogiannis NG. Why animal model studies are lost in translation. J Cardiovasc Aging. 2022;2. doi: 10.20517/jca.2022.10
  • Frangogiannis NG. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 2014;11(5):255–65. doi: 10.1038/nrcardio.2014.28
  • Khalil H, Kanisicak O, Prasad V, et al. Fibroblast-specific TGF-β–Smad2/3 signaling underlies cardiac fibrosis. J Clin Invest. 2017;127(10):3770–3783. doi: 10.1172/JCI94753
  • Tuleta I, Frangogiannis NG. Fibrosis of the diabetic heart: clinical significance, molecular mechanisms, and therapeutic opportunities. Adv Drug Deliv Rev. 2021;176:113904. doi: 10.1016/j.addr.2021.113904
  • Derangeon M, Montnach J, Cerpa CO, et al. Transforming growth factor β receptor inhibition prevents ventricular fibrosis in a mouse model of progressive cardiac conduction disease. Cardiovasc Res. 2017;113(5):464–474. doi: 10.1093/cvr/cvx026
  • Biernacka A, Frangogiannis NG. Aging and cardiac fibrosis. Aging Dis. 2011;2:158–173.
  • Sano S, Horitani K, Ogawa H, et al. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Science. 2022;377(6603):292–7. doi: 10.1126/science.abn3100
  • Diez J, Gonzalez A, Kovacic JC. Myocardial interstitial fibrosis in nonischemic heart disease, part 3/4: JACC focus seminar. J Am Coll Cardiol. 2020;75(17):2204–18. doi: 10.1016/j.jacc.2020.03.019
  • Matsa E, Sallam K, Wu JC. Cardiac stem cell biology: glimpse of the past, present, and future. Circ Res. 2014;114(1):21–7. doi: 10.1161/CIRCRESAHA.113.302895
  • Laflamme MA, Murry CE. Heart regeneration. Nature. 2011;473(7347):326–35. doi: 10.1038/nature10147
  • Heallen TR, Kadow ZA, Kim JH, et al. Stimulating cardiogenesis as a treatment for Heart failure. Circ Res. 2019;124(11):1647–57. doi: 10.1161/CIRCRESAHA.118.313573
  • Karbassi E, Fenix A, Marchiano S, et al. Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine. Nat Rev Cardiol. 2020;17(6):341–59. doi: 10.1038/s41569-019-0331-x
  • Behfar A, Zingman LV, Hodgson DM, et al. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J. 2002;16(12):1558–66. doi: 10.1096/fj.02-0072com
  • Goumans MJ, de Boer TP, Smits AM, et al. TGF-β1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res. 2007;1(2):138–149. doi: 10.1016/j.scr.2008.02.003
  • Chablais F, Jazwinska A. The regenerative capacity of the zebrafish heart is dependent on TGFβ signaling. Development. 2012;139(11):1921–1930. doi: 10.1242/dev.078543
  • Chen WP, Liu YH, Ho YJ, et al. Pharmacological inhibition of TGFβ receptor improves Nkx2.5 cardiomyoblast-mediated regeneration. Cardiovasc Res. 2015;105(1):44–54. doi: 10.1093/cvr/cvu229
  • Mohamed TMA, Ang YS, Radzinsky E, et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell. 2018;173(1):104–16 e12. doi: 10.1016/j.cell.2018.02.014
  • Willems E, Cabral-Teixeira J, Schade D, et al. Small molecule-mediated TGF-β type II receptor degradation promotes cardiomyogenesis in embryonic stem cells. Cell Stem Cell. 2012;11(2):242–252. doi: 10.1016/j.stem.2012.04.025
  • Keepers B, Liu J, Qian L. What’s in a cardiomyocyte – and how do we make one through reprogramming? Biochim Biophys Acta, Mol Cell Res. 2020;1867(3):118464. doi: 10.1016/j.bbamcr.2019.03.011
  • Wang Q, Spurlock B, Liu J, et al. Fibroblast reprogramming in cardiac repair. JACC Basic Transl Sci. 2023;9(1):145–160. doi: 10.1016/j.jacbts.2023.06.012
  • Riching AS, Danis E, Zhao Y, et al. Suppression of canonical TGF-beta signaling enables GATA4 to interact with H3K27me3 demethylase JMJD3 to promote cardiomyogenesis. J Mol Cell Cardiol. 2020;153:44–59. doi: 10.1016/j.yjmcc.2020.12.005
  • Yamakawa H, Ieda M. Cardiac regeneration by direct reprogramming in this decade and beyond. Inflamm Regen. 2021;41(1):20. doi: 10.1186/s41232-021-00168-5

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.