Heart Failure Reviews

, Volume 24, Issue 1, pp 1–15 | Cite as

Biomarkers for the identification of cardiac fibroblast and myofibroblast cells

  • Emiri Tarbit
  • Indu Singh
  • Jason N. Peart
  • Roselyn B. Rose’MeyerEmail author


Experimental research has recognized the importance of cardiac fibroblast and myofibroblast cells in heart repair and function. In a normal healthy heart, the cardiac fibroblast plays a central role in the structural, electrical, and chemical aspects within the heart. Interestingly, the transformation of cardiac fibroblast cells to cardiac myofibroblast cells is suspected to play a vital part in the development of heart failure. The ability to differentiate between the two cells types has been a challenge. Myofibroblast cells are only expressed in the stressed or failing heart, so a better understanding of cell function may identify therapies that aid repair of the damaged heart. This paper will provide an outline of what is currently known about cardiac fibroblasts and myofibroblasts, the physiological and pathological roles within the heart, and causes for the transition of fibroblasts into myoblasts. We also reviewed the potential markers available for characterizing these cells and found that there is no single-cell specific marker that delineates fibroblast or myofibroblast cells. To characterize the cells of fibroblast origin, vimentin is commonly used. Cardiac fibroblasts can be identified using discoidin domain receptor 2 (DDR2) while α-smooth muscle actin is used to distinguish myofibroblasts. A known cytokine TGF-β1 is well established to cause the transformation of cardiac fibroblasts to myofibroblasts. This review will also discuss clinical treatments that inhibit or reduce the actions of TGF-β1 and its contribution to cardiac fibrosis and heart failure.


Cardiac fibroblast Cardiac myofibroblast Biomarkers Alpha-smooth muscle actin Heart failure 



There is no external funding for this project.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Roth GA, Huffman MD, Moran AE, Feigin V, Mensah GA, Naghavi M, Murray CJ (2015) Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation 132(17):1667–1678. CrossRefPubMedGoogle Scholar
  2. 2.
    Cohn JN, Ferrari R, Sharpe N (2000) Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf An Int Forum Cardiac Remodeling J Am Coll Cardiol 35(3):569–582Google Scholar
  3. 3.
    Azevedo PS, Polegato BF, Minicucci MF, Paiva SAR, Zornoff LAM (2016) Cardiac remodeling: concepts, clinical impact. Pathophysiological Mechanisms Pharmacologic Treatment Arquivos Brasileiros de Cardiologia 106(1):62–69. CrossRefPubMedGoogle Scholar
  4. 4.
    Camelliti P, Borg TK, Kohl P (2005) Structural and functional characterisation of cardiac fibroblasts. Cardiovasc Res 65(1):40–51. CrossRefPubMedGoogle Scholar
  5. 5.
    Souders CA, Bowers SLK, Baudino TA (2009) Cardiac Fibroblast. Renaissance Cell 105(12):1164–1176. CrossRefGoogle Scholar
  6. 6.
    Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC (2016) Cardiac fibrosis: the fibroblast awakens. Circ Res 118(6):1021–1040. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Santiago JJ, Dangerfield AL, Rattan SG, Bathe KL, Cunnington RH, Raizman JE, Bedosky KM, Freed DH, Kardami E, Dixon IM (2010) Cardiac fibroblast to myofibroblast differentiation in vivo and in vitro: expression of focal adhesion components in neonatal and adult rat ventricular myofibroblasts. Developmental Dynamics : an Official Publication Am Assoc Anatomists 239(6):1573–1584. CrossRefGoogle Scholar
  8. 8.
    Souders CA, Bowers SLK, Baudino TA (2009) Cardiac fibroblast: the renaissance cell. Circ Res 105(12):1164–1176. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Nag AC (1980) Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios 28(109):41–61PubMedGoogle Scholar
  10. 10.
    Porter K, Turner N (2009) Cardiac fibroblasts: at the heart of myocardial remodeling. Pharmacol Therapeut 123(2):255–278. CrossRefGoogle Scholar
  11. 11.
    Vliegen HW, Van Der Laarse A, Cornelisse CJ, Eulderink F (1991) Myocardial changes in pressure overload-induced left ventricular hypertrophy: a study on tissue composition, polyploidization and multinucleation. European Heart J 12(4):488–494. CrossRefGoogle Scholar
  12. 12.
    Shinde AV, Frangogiannis NG (2014) Fibroblasts in myocardial infarction: a role in inflammation and repair. J Mol Cell Cardiol 70:74–82. CrossRefPubMedGoogle Scholar
  13. 13.
    Baudino TA, Carver W, Giles W, Borg TK (2006) Cardiac fibroblasts: friend or foe? Am J Physiol Heart Circ Physiol 291(3):1015–1026. CrossRefGoogle Scholar
  14. 14.
    MacKenna D, Summerour SR, Villarreal FJ (2000) Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc Res 46(2):257–263. CrossRefPubMedGoogle Scholar
  15. 15.
    Zeisberg EM, Kalluri R (2010) Origins of cardiac fibroblasts. Circ Res 107(11):1304–1312. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Fan D, Takawale A, Lee J, Kassiri Z (2012) Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair 5(1):15CrossRefGoogle Scholar
  17. 17.
    Shamhart PE, Naugle JE, Olson ER, Hruska MA, Doane KJ, Meszaros JG (2007) Cardiac fibroblast migration during in vitro wound healing: the role of specific collagen substrates. FASEB J 21(6):1428–1429Google Scholar
  18. 18.
    McSpadden LC, Kirkton RD, Bursac N (2009) Electrotonic loading of anisotropic cardiac monolayers by unexcitable cells depends on connexin type and expression level. Am J Physiol Cell Physiol 297(2):C339–C351. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Muñoz V, Campbell K, Shibayama J (2008) Fibroblasts: modulating the rhythm of the heart. J Physiol 586(10):2423–2424. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yue L, Xie J, Nattel S (2011) Molecular determinants of cardiac fibroblast electrical function and therapeutic implications for atrial fibrillation. Cardiovasc Res 89(4):744–753. CrossRefPubMedGoogle Scholar
  21. 21.
    Camelliti P, Green CR, LeGrice I, Kohl P (2004) Fibroblast network in rabbit sinoatrial node: structural and functional identification of homogeneous and heterogeneous cell coupling. Circ Res 94(6):828–835. CrossRefPubMedGoogle Scholar
  22. 22.
    Rudy Y (2004) Conductive bridges in cardiac tissue: a beneficial role or an Arrhythmogenic substrate? Circ Res 94(6):709–711. CrossRefPubMedGoogle Scholar
  23. 23.
    Kohl P, Camelliti P, Burton FL, Smith GL (2005) Electrical coupling of fibroblasts and myocytes: relevance for cardiac propagation. J Electrocardiol 38(4S):45–50CrossRefGoogle Scholar
  24. 24.
    Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA (2005) Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci U S A 102(2):437–442. CrossRefPubMedGoogle Scholar
  25. 25.
    Lijnen P, Petrov V (2002) Transforming growth factor-beta 1-induced collagen production in cultures of cardiac fibroblasts is the result of the appearance of myofibroblasts. Methods Find Exp Clin Pharmacol 24(6):333–344. CrossRefPubMedGoogle Scholar
  26. 26.
    Santiago JJ, Dangerfield AL, Rattan SG, Bathe KL, Cunnington RH, Raizman JE, Bedosky KM, Freed DH, Kardami E, Dixon I (2010) Cardiac fibroblast to myofibroblast differentiation in vivo and in vitro: expression of focal adhesion components in neonatal and adult rat ventricular myofibroblasts. Dev Dyn 239(6):1573–1584. CrossRefPubMedGoogle Scholar
  27. 27.
    Baum J, Duffy HS (2011) Fibroblasts and myofibroblasts: what are we talking about? J Cardiovasc Pharmacol 57(4):376–379. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Roy SG, Nozaki Y, Phan SH (2001) Regulation of α-smooth muscle actin gene expression in myofibroblast differentiation from rat lung fibroblasts. Int J Biochem Cell Biol 33(7):723–734. CrossRefPubMedGoogle Scholar
  29. 29.
    Ehrlich HP, Allison GM, Leggett M (2006) The myofibroblast, cadherin, alpha smooth muscle actin and the collagen effect. Cell Biochem Funct 24(1):63–70. CrossRefPubMedGoogle Scholar
  30. 30.
    Nakaya M, Watari K, Tajima M, Nakaya T, Matsuda S, Ohara H, Nishihara H, Yamaguchi H, Hashimoto A, Nishida M, Nagasaka A, Horii Y, Ono H, Iribe G, Inoue R, Tsuda M, Inoue K, Tanaka A, Kuroda M, Nagata S, Kurose H (2017) Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. J Clin Invest 127(1):383–401. CrossRefPubMedGoogle Scholar
  31. 31.
    Bergmann MW (2010) WNT signaling in adult cardiac hypertrophy and remodeling lessons learned from cardiac development. Circ Res 107(10):1198–1208. CrossRefPubMedGoogle Scholar
  32. 32.
    MacLean J, Pasumarthi KB (2014) Signaling mechanisms regulating fibroblast activation, phenoconversion and fibrosis in the heart. Indian J Biochem Biophys 51(6):476–482PubMedGoogle Scholar
  33. 33.
    Liu S, Xu SW, Kennedy L, Pala D, Chen Y, Eastwood M, Carter DE, Black CM, Abraham DJ, Leask A (2007) FAK is required for TGFbeta-induced JNK phosphorylation in fibroblasts: implications for acquisition of a matrix-remodeling phenotype. Mol Biol Cell 18(6):2169–2178. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Komiya Y, Habas R (2008) Wnt signal transduction pathways. Organogenesis 4(2):68–75. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cohen ED, Tian Y, Morrisey EE (2008) Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self-renewal. Development 135(5):789–798. CrossRefPubMedGoogle Scholar
  36. 36.
    Dawson K, Aflaki M, Nattel S (2013) Role of the Wnt-frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential. J Physiol 591(Pt 6):1409–1432. CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang D, Gaussin V, Taffet GE, Belaguli NS, Yamada M, Schwartz RJ, Michael LH, Overbeek PA, Schneider MD (2000) TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat Med 6(5):556–563. CrossRefPubMedGoogle Scholar
  38. 38.
    Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat M-L, Gabbiani G (2007) The Myofibroblast: one function, multiple origins. Am J Pathol 170(6):1807–1816. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Dobaczewski M, Chen W, Frangogiannis NG (2010) Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol 51(4):600–606. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA (2011) Latent TGF-β structure and activation. Nature 474(7351):343–349. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Blakytny R, Ludlow A, Martin G, Ireland G, Lund LR, Ferguson M, Brunner G (2004) Latent TGF-β1 activation by platelets. J Cell Physiol 199(1):67–76. CrossRefPubMedGoogle Scholar
  42. 42.
    Taylor AW (2009) Review of the activation of TGF-beta in immunity. J Leukoc Biol 85(1):29–33. CrossRefPubMedGoogle Scholar
  43. 43.
    Folger PA, Zekaria D, Grotendorst G, Masur SK (2001) Transforming growth factor-beta-stimulated connective tissue growth factor expression during corneal myofibroblast differentiation. Invest Ophthalmol Vis Sci 42(11):2534–2541PubMedGoogle Scholar
  44. 44.
    Hinz B (2007) Formation and function of the Myofibroblast during tissue repair. J Investig Dermatol 127(3):526–537. CrossRefPubMedGoogle Scholar
  45. 45.
    Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP, Iredale JP, Haslett C, Simpson KJ, Sethi T (2006) Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc Natl Acad Sci U S A 103(13):5060–5065. CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Shephard P, Martin G, Smola-Hess S, Brunner G (2004) Myofibroblast differentiation is induced in keratinocyte-fibroblast co-cultures and is antagonistically regulated by endogenous transforming growth factor-β and Interleukin-1. Am J Pathol 164(6):2055–2066. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gallucci RM, Lee EG, Tomasek JJ (2006) IL-6 modulates alpha-smooth muscle actin expression in dermal fibroblasts from IL-6-deficient mice. J Investigative Dermatology 126(3):561–568. CrossRefGoogle Scholar
  48. 48.
    Bujak M, Frangogiannis NG (2007) The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res 74(2):184–195. CrossRefPubMedGoogle Scholar
  49. 49.
    Li P, Wang D, Lucas J, Oparil S, Xing D, Cao X, Novak L, Renfrow MB, Chen Y-F (2008) Atrial natriuretic peptide inhibits transforming growth factor –induced smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res 102(2):185–192. CrossRefPubMedGoogle Scholar
  50. 50.
    Vivar R, Humeres C, Ayala P, Olmedo I, Catalán M, García L, Lavandero S, Díaz-Araya G (2013) TGF-β1 prevents simulated ischemia/reperfusion-induced cardiac fibroblast apoptosis by activation of both canonical and non-canonical signaling pathways. Biochim Biophys Acta (BBA) - Mol Basis Dis 1832(6):754–762. CrossRefGoogle Scholar
  51. 51.
    Phan SH (2008) Biology of fibroblasts and myofibroblasts. Proc Am Thorac Soc 5(3):334–337. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Talman V, Ruskoaho H (2016) Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration. Cell Tissue Res 365(3):563–581. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Aurora AB, Porrello ER, Tan W, Mahmoud AI, Hill JA, Bassel-Duby R, Sadek HA, Olson EN (2014) Macrophages are required for neonatal heart regeneration. J Clin Investig 124(3):1382–1392. CrossRefPubMedGoogle Scholar
  54. 54.
    Saxena A, Chen W, Su Y, Rai V, Uche OU, Li N, Frangogiannis NG (2013) IL-1 induces proinflammatory leukocyte infiltration and regulates fibroblast phenotype in the infarcted myocardium. J Immunology (Baltimore, Md : 1950) 191(9):4838–4848. CrossRefGoogle Scholar
  55. 55.
    Frangogiannis NG (2014) The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 11(5):255–265. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    van den Borne SWM, Diez J, Blankesteijn WM, Verjans J, Hofstra L, Narula J (2010) Myocardial remodeling after infarction: the role of myofibroblasts. Nat Rev Cardiol 7(1):30–37CrossRefGoogle Scholar
  57. 57.
    Van Linthout S, Miteva K, Tschöpe C (2014) Crosstalk between fibroblasts and inflammatory cells. Cardiovasc Res 102(2):258–269. CrossRefPubMedGoogle Scholar
  58. 58.
    Bai J, Zhang N, Hua Y, Wang B, Ling L, Ferro A, Xu B (2013) Metformin inhibits angiotensin II-induced differentiation of cardiac fibroblasts into Myofibroblasts. PLoS One 8(9):e72120. CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Cheng T-HH, Cheng P-YY, Shih N-LL, Chen I-BB, Wang DL, Chen J-JJ (2003) Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts. J Am Coll Cardiol 42(10):1845–1854CrossRefGoogle Scholar
  60. 60.
    Lijnen PJ, van Pelt JF, Fagard RH (2012) Stimulation of reactive oxygen species and collagen synthesis by angiotensin II in cardiac fibroblasts. Cardiovasc Ther 30(1):8–e8. CrossRefGoogle Scholar
  61. 61.
    Jiang F, Liu G-S, Dusting GJ, Chan EC (2014) NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox Biol 2:267–272. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Thannickal VJ (2010) Aging, antagonistic pleiotropy and fibrotic disease. Int J Biochem Cell Biol 42(9):1398–1400. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Murphy AM, Wong AL, Bezuhly M (2015) Modulation of angiotensin II signaling in the prevention of fibrosis. Fibrogenesis Tissue Repair 8(1):7. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Wang J, Chen H, Seth A, McCulloch CA (2003) Mechanical force regulation of myofibroblast differentiation in cardiac fibroblasts. Am J Physiol Heart Circ Physiol 285(5):1871–1881. CrossRefGoogle Scholar
  65. 65.
    Gazoti Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R (2001) Age related changes of the collagen network of the human heart. Mech Ageing Dev 122(10):1049–1058. CrossRefPubMedGoogle Scholar
  66. 66.
    Cieslik KA, Trial J, Crawford JR, Taffet GE, Entman ML (2014) Adverse fibrosis in the aging heart depends on signaling between myeloid and mesenchymal cells; role of inflammatory fibroblasts. J Mol Cell Cardiol 0:56–63. CrossRefGoogle Scholar
  67. 67.
    Chiao YA, Ramirez TA, Zamilpa R, Okoronkwo SM, Dai Q, Zhang J, Jin Y-F, Lindsey ML (2012) Matrix metalloproteinase-9 deletion attenuates myocardial fibrosis and diastolic dysfunction in ageing mice. Cardiovasc Res 96(3):444–455. CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Segers VFM, Lee RT (2010) Protein therapeutics for cardiac regeneration after myocardial infarction. J Cardiovasc Transl Res 3(5):469–477. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Strait JB, Lakatta EG (2012) Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail Clin 8(1):143–164. CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Masur SK, Dewal HS, Dinh TT, Erenburg I, Petridou S (1996) Myofibroblasts differentiate from fibroblasts when plated at low density. Proc Natl Acad Sci 93(9):4219–4223. CrossRefPubMedGoogle Scholar
  71. 71.
    Chang HY, Chi J-T, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO (2002) Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci 99(20):12877–12882. CrossRefPubMedGoogle Scholar
  72. 72.
    Moore-Morris T, Guimarães-Camboa N, Yutzey KE, Pucéat M, Evans SM (2015) Cardiac fibroblasts: from development to heart failure. J Molecular Medicine (Berlin, Germany) 93(8):823–830. CrossRefGoogle Scholar
  73. 73.
    Doppler SA, Carvalho C, Lahm H, Deutsch M-A, Dreßen M, Puluca N, Lange R, Krane M (2017) Cardiac fibroblasts: more than mechanical support. J Thoracic Disease 9:S36–S51CrossRefGoogle Scholar
  74. 74.
    Ivey MJ, Tallquist MD (2016) Defining the cardiac fibroblast. Circ J 80(11):2269–2276. CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Turner NA, Porter KE (2013) Function and fate of myofibroblasts after myocardial infarction. Fibrogenesis Tissue Repair 6(1):5. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Zahradka P (2008) Novel role for osteopontin in cardiac fibrosis. Circ Res 102(3):270–272. CrossRefPubMedGoogle Scholar
  77. 77.
    Tamaoki M, Imanaka-Yoshida K, Yokoyama K, Nishioka T, Inada H, Hiroe M, Sakakura T, Yoshida T (2005) Tenascin-C regulates recruitment of Myofibroblasts during tissue repair after myocardial injury. Am J Pathol 167(1):71–80CrossRefGoogle Scholar
  78. 78.
    Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, Saito M, Fukuda K, Nishiyama T, Kitajima S, Saga Y, Fukayama M, Sata M, Kudo A (2008) Periostin is essential for cardiac healingafter acute myocardial infarction. J Exp Med 205(2):295–303. CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Zhao S, Wu H, Xia W, Chen X, Zhu S, Zhang S, Shao Y, Ma W, Yang D, Zhang J (2014) Periostin expression is upregulated and associated with myocardial fibrosis in human failing hearts. J Cardiol 63(5):373–378. CrossRefPubMedGoogle Scholar
  80. 80.
    Snider P, Standley KN, Wang J, Azhar M, Doetschman T, Conway SJ (2009) Origin of cardiac fibroblasts and the role of periostin. Circ Res 105(10):934–947. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Kanisicak O, Khalil H, Ivey MJ, Karch J, Maliken BD, Correll RN, Brody MJ, J Lin SC, Aronow BJ, Tallquist MD, Molkentin JD (2016) Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nature Communications 7:12260. CrossRefPubMedPubMedCentralGoogle Scholar
  82. 83.
    Leslie KO, Taatjes DJ, Schwarz J, vonTurkovich M, Low RB (1991) Cardiac myofibroblasts express alpha smooth muscle actin during right ventricular pressure overload in the rabbit. Am J Pathol 139(1):207–216PubMedPubMedCentralGoogle Scholar
  83. 84.
    Ma Y, Iyer RP, Jung M, Czubryt MP, Lindsey ML (2017) Cardiac fibroblast activation post-myocardial infarction: current knowledge gaps. Trends Pharmacol Sci 38(5):448–458. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 85.
    Chen W, Frangogiannis NG (2013) Fibroblasts in post-infarction inflammation and cardiac repair. Biochim Biophys Acta 1833(4):945–953. CrossRefPubMedGoogle Scholar
  85. 86.
    Villarreal FJ, Kim NN, Ungab GD, Printz MP, Dillmann WH (1993) Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 88(6):2849–2861CrossRefGoogle Scholar
  86. 87.
    Bursac N (2014) Cardiac fibroblasts in pressure overload hypertrophy: the enemy within? J Clin Investig 124(7):2850–2853. CrossRefPubMedGoogle Scholar
  87. 88.
    Moore-Morris T, Guimarães-Camboa N, Banerjee I, Zambon AC, Kisseleva T, Velayoudon A, Stallcup WB, Gu Y, Dalton ND, Cedenilla M, Gomez-Amaro R, Zhou B, Brenner DA, Peterson KL, Chen J, Evans SM (2014) Resident fibroblast lineages mediate pressure overload–induced cardiac fibrosis. J Clin Invest 124(7):2921–2934. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 89.
    Ashizawa N, Graf K, Do YS, Nunohiro T, Giachelli CM, Meehan WP, Tuan TL, Hsueh WA (1996) Osteopontin is produced by rat cardiac fibroblasts and mediates a(II)-induced DNA synthesis and collagen gel contraction. J Clin Investig 98(10):2218–2227CrossRefGoogle Scholar
  89. 90.
    Snider P, Standley KN, Wang J, Azhar M, Doetschman T, Conway SJ (2009) Origin of cardiac fibroblasts and the role of Periostin. Circ Res 105(10):934–947. CrossRefPubMedPubMedCentralGoogle Scholar
  90. 91.
    Donovan J, Shiwen X, Norman J, Abraham D (2013) Platelet-derived growth factor alpha and beta receptors have overlapping functional activities towards fibroblasts. Fibrogenesis Tissue Repair 6:10–10. CrossRefPubMedPubMedCentralGoogle Scholar
  91. 92.
    Sun W, Zhang H, Guo J, Zhang X, Zhang L, Li C, Zhang L (2016) Comparison of the efficacy and safety of different ACE inhibitors in patients with chronic heart failure: a PRISMA-compliant network meta-analysis. Medicine 95(6):e2554. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 93.
    Ellmers LJ, Scott NJ, Medicherla S, Pilbrow AP, Bridgman PG, Yandle TG, Richards AM, Protter AA, Cameron VA (2008) Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction. Endocrinology 149(11):5828–5834. CrossRefPubMedGoogle Scholar
  93. 94.
    Li L, Bounds KR, Chatterjee P, Gupta S (2017) MicroRNA-130a, a potential Antifibrotic target in cardiac fibrosis. J Am Heart Assoc 6(11):e006763. CrossRefPubMedPubMedCentralGoogle Scholar
  94. 95.
    Mann DL, McMurray JJ, Packer M, Swedberg K, Borer JS, Colucci WS, Djian J, Drexler H, Feldman A, Kober L, Krum H, Liu P, Nieminen M, Tavazzi L, van Veldhuisen DJ, Waldenstrom A, Warren M, Westheim A, Zannad F, Fleming T (2004) Targeted anticytokine therapy in patients with chronic heart failure: results of the randomized Etanercept worldwide evaluation (RENEWAL). Circulation 109(13):1594–1602. CrossRefPubMedGoogle Scholar
  95. 96.
    Brilla CG, Funck RC, Rupp H (2000) Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation 102(12):1388–1393CrossRefGoogle Scholar
  96. 97.
    Diez J, Querejeta R, Lopez B, Gonzalez A, Larman M, Martinez Ubago JL (2002) Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation 105(21):2512–2517CrossRefGoogle Scholar
  97. 98.
    Shimada YJ, Passeri JJ, Baggish AL, O’Callaghan C, Lowry PA, Yannekis G, Abbara S, Ghoshhajra BB, Rothman RD, Ho CY, Januzzi JL, Seidman CE, Fifer MA (2013) Effects of losartan on left ventricular hypertrophy and fibrosis in patients with nonobstructive hypertrophic cardiomyopathy. JACC Heart failure 1(6):480–487. CrossRefPubMedPubMedCentralGoogle Scholar
  98. 99.
    Mendell JR, Sahenk Z, Al-Zaidy S, Rodino-Klapac LR, Lowes LP, Alfano LN, Berry K, Miller N, Yalvac M, Dvorchik I, Moore-Clingenpeel M, Flanigan KM, Church K, Shontz K, Curry C, Lewis S, McColly M, Hogan MJ, Kaspar BK (2017) Follistatin gene therapy for sporadic inclusion body myositis improves functional outcomes. Mol Ther 25(4):870–879. CrossRefPubMedPubMedCentralGoogle Scholar
  99. 100.
    Martin J, Kelly DJ, Mifsud SA, Zhang Y, Cox AJ, See F, Krum H, Wilkinson-Berka J, Gilbert RE (2005) Tranilast attenuates cardiac matrix deposition in experimental diabetes: role of transforming growth factor-β. Cardiovasc Res 65(3):694–701. CrossRefPubMedGoogle Scholar
  100. 101.
    Hocher B, Godes M, Olivier J, Weil J, Eschenhagen T, Slowinski T, Neumayer HH, Bauer C, Paul M, Pinto YM (2002) Inhibition of left ventricular fibrosis by tranilast in rats with renovascular hypertension. J Hypertens 20(4):745–751CrossRefGoogle Scholar
  101. 102.
    Hager M, Pedersen CC, Larsen MT, Andersen MK, Hother C, Gronbaek K, Jarmer H, Borregaard N, Cowland JB (2011) MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-beta1 stimulation in granulocytic precursors. Blood 118(25):6649–6659. CrossRefPubMedGoogle Scholar
  102. 103.
    Tijsen AJ, van der Made I, van den Hoogenhof MM, Wijnen WJ, van Deel ED, de Groot NE, Alekseev S, Fluiter K, Schroen B, Goumans M-J, van der Velden J, Duncker DJ, Pinto YM, Creemers EE (2014) The microRNA-15 family inhibits the TGFβ-pathway in the heart. Cardiovasc Res 104(1):61–71. CrossRefPubMedGoogle Scholar
  103. 104.
    Giam B, Chu PY, Kuruppu S, Smith AI, Horlock D, Kiriazis H, Du XJ, Kaye DM, Rajapakse NW (2016) N-acetylcysteine attenuates the development of cardiac fibrosis and remodeling in a mouse model of heart failure. Physiological Reports 4(7):e12757. CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Emiri Tarbit
    • 1
  • Indu Singh
    • 1
  • Jason N. Peart
    • 1
  • Roselyn B. Rose’Meyer
    • 1
    Email author
  1. 1.School of Medical SciencesGriffith UniversityGriffithAustralia

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