Aging-Associated Alterations in Myocardial Inflammation and Fibrosis: Pathophysiological Perspectives and Clinical Implications

  • Arti V. Shinde
  • Nikolaos G. FrangogiannisEmail author


Senescent hearts exhibit structural and molecular changes that result in impaired function and are associated with diminished ability to meet increased demand. Both animal model studies and clinical investigations suggest that fibrosis is a hallmark of cardiac aging. Expansion of the cardiac interstitium and accumulation of collagen in the aging heart cause a progressive increase in ventricular stiffness, contributing to impaired diastolic function. Increased mechanical load due to increased vascular stiffness and direct activation of senescence-associated fibrogenic signals in the myocardium are implicated in the pathogenesis of cardiac fibrosis in the elderly. Reactive oxygen species (ROS), chemokine-mediated recruitment of mononuclear cells and fibroblast progenitors, transforming growth factor (TGF)-β activation, and angiotensin II signaling may be essential mediators of interstitial and perivascular fibrosis in the senescent heart. Reduced collagen degradation may be more important than increased matrix protein synthesis in the pathogenesis of aging-associated fibrosis. In addition to an age-related baseline activation of inflammatory and profibrotic signals, senescence is also associated with a suppressed and prolonged inflammatory reaction after myocardial injury and with defective activation of reparative fibroblasts in response to growth factors. These reparative defects impair scar formation and may promote adverse dilative remodeling. Understanding the involvement of inflammatory and fibrogenic mediators in repair and remodeling of the aging heart is critical in order to design new strategies for prevention of heart failure in elderly patients.


Diastolic Dysfunction Cardiac Fibroblast Cardiac Fibrosis Infarcted Heart Cardiomyocyte Hypertrophy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr. Frangogiannis’ laboratory is supported by NIH grants R01 HL-76246 and R01 HL-85440, the Wilf Family Cardiovascular Research Institute, and the Edmond J. Safra/Republic National Bank of New York Chair in Cardiovascular Medicine.


  1. 1.
    Vigen R, Maddox TM, Allen LA. Aging of the United States population: impact on heart failure. Curr Heart Fail Rep. 2012;9:369–74.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125:e2–e220.PubMedGoogle Scholar
  3. 3.
    Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123:933–44.PubMedGoogle Scholar
  4. 4.
    Vanoverschelde JJ, Essamri B, Vanbutsele R, et al. Contribution of left ventricular diastolic function to exercise capacity in normal subjects. J Appl Physiol. 1993;74:2225–33.PubMedGoogle Scholar
  5. 5.
    Biernacka A, Frangogiannis NG. Aging and cardiac fibrosis. Aging Dis. 2011;2:158–73.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Chen W, Frangogiannis NG. The role of inflammatory and fibrogenic pathways in heart failure associated with aging. Heart Fail Rev. 2010;15:415–22.PubMedCentralPubMedGoogle Scholar
  7. 7.
    Mukherjee D, Sen S. Collagen phenotypes during development and regression of myocardial hypertrophy in spontaneously hypertensive rats. Circ Res. 1990;67:1474–80.PubMedGoogle Scholar
  8. 8.
    Dai DF, Chen T, Johnson SC, Szeto H, Rabinovitch PS. Cardiac aging: from molecular mechanisms to significance in human health and disease. Antioxid Redox Signal. 2012;16:1492–526.PubMedGoogle Scholar
  9. 9.
    Burlew BS. Diastolic dysfunction in the elderly–the interstitial issue. Am J Geriatr Cardiol. 2004;13:29–38.PubMedGoogle Scholar
  10. 10.
    Nag AC. Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution. Cytobios. 1980;28:41–61.PubMedGoogle Scholar
  11. 11.
    Souders CA, Bowers SL, Baudino TA. Cardiac fibroblast: the renaissance cell. Circ Res. 2009;105:1164–76.PubMedCentralPubMedGoogle Scholar
  12. 12.
    Dobaczewski M, de Haan JJ, Frangogiannis NG. The extracellular matrix modulates fibroblast phenotype and function in the infarcted myocardium. J Cardiovasc Transl Res. 2012;5(6):837–47.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Tian Y, Morrisey EE. Importance of myocyte-nonmyocyte interactions in cardiac development and disease. Circ Res. 2012;110:1023–34.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest. 2007;117:568–75.PubMedCentralPubMedGoogle Scholar
  15. 15.
    Isoyama S, Nitta-Komatsubara Y. Acute and chronic adaptation to hemodynamic overload and ischemia in the aged heart. Heart Fail Rev. 2002;7:63–9.PubMedGoogle Scholar
  16. 16.
    Pugh KG, Wei JY. Clinical implications of physiological changes in the aging heart. Drugs Aging. 2001;18:263–76.PubMedGoogle Scholar
  17. 17.
    Chen MA. Heart failure with preserved ejection fraction in older adults. Am J Med. 2009;122:713–23.PubMedGoogle Scholar
  18. 18.
    Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560–8.PubMedGoogle Scholar
  19. 19.
    Kajstura J, Cheng W, Sarangarajan R, et al. Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats. Am J Physiol. 1996;271:H1215–1228.PubMedGoogle Scholar
  20. 20.
    Anversa P, Palackal T, Sonnenblick EH, et al. Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res. 1990;67:871–85.PubMedGoogle Scholar
  21. 21.
    Eghbali M, Robinson TF, Seifter S, Blumenfeld OO. Collagen accumulation in heart ventricles as a function of growth and aging. Cardiovasc Res. 1989;23:723–9.PubMedGoogle Scholar
  22. 22.
    Horn MA, Graham HK, Richards MA, et al. Age-related divergent remodeling of the cardiac extracellular matrix in heart failure: collagen accumulation in the young and loss in the aged. J Mol Cell Cardiol. 2012;53:82–90.PubMedGoogle Scholar
  23. 23.
    Orlandi A, Francesconi A, Marcellini M, Ferlosio A, Spagnoli LG. Role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit. Cardiovasc Res. 2004;64:544–52.PubMedGoogle Scholar
  24. 24.
    Lin J, Lopez EF, Jin Y, et al. Age-related cardiac muscle sarcopenia: combining experimental and mathematical modeling to identify mechanisms. Exp Gerontol. 2008;43:296–306.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Gazoti Debessa CR, Mesiano Maifrino LB, Rodrigues de Souza R. Age related changes of the collagen network of the human heart. Mech Ageing Dev. 2001;122:1049–58.PubMedGoogle Scholar
  26. 26.
    de Souza RR. Aging of myocardial collagen. Biogerontology. 2002;3:325–35.PubMedGoogle Scholar
  27. 27.
    Lakatta EG. Age-associated cardiovascular changes in health: impact on cardiovascular disease in older persons. Heart Fail Rev. 2002;7:29–49.PubMedGoogle Scholar
  28. 28.
    Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol Rev. 2007;87:1285–342.PubMedGoogle Scholar
  29. 29.
    Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007;74:184–95.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Bujak M, Dobaczewski M, Chatila K, et al. Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling. Am J Pathol. 2008;173:57–67.PubMedGoogle Scholar
  31. 31.
    Siwik DA, Chang DL, Colucci WS. Interleukin-1beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circ Res. 2000;86:1259–65.PubMedGoogle Scholar
  32. 32.
    Mays PK, McAnulty RJ, Campa JS, Laurent GJ. Age-related changes in collagen synthesis and degradation in rat tissues. Importance of degradation of newly synthesized collagen in regulating collagen production. Biochem J. 1991;276(Pt 2):307–13.PubMedGoogle Scholar
  33. 33.
    Besse S, Robert V, Assayag P, Delcayre C, Swynghedauw B. Nonsynchronous changes in myocardial collagen mRNA and protein during aging: effect of DOCA-salt hypertension. Am J Physiol. 1994;267:H2237–2244.PubMedGoogle Scholar
  34. 34.
    Annoni G, Luvara G, Arosio B, et al. Age-dependent expression of fibrosis-related genes and collagen deposition in the rat myocardium. Mech Ageing Dev. 1998;101:57–72.PubMedGoogle Scholar
  35. 35.
    Robert V, Besse S, Sabri A, et al. Differential regulation of matrix metalloproteinases associated with aging and hypertension in the rat heart. Lab Invest. 1997;76:729–38.PubMedGoogle Scholar
  36. 36.
    Thomas DP, Cotter TA, Li X, McCormick RJ, Gosselin LE. Exercise training attenuates aging-associated increases in collagen and collagen crosslinking of the left but not the right ventricle in the rat. Eur J Appl Physiol. 2001;85:164–9.PubMedGoogle Scholar
  37. 37.
    Thomas DP, Zimmerman SD, Hansen TR, Martin DT, McCormick RJ. Collagen gene expression in rat left ventricle: interactive effect of age and exercise training. J Appl Physiol. 2000;89:1462–8.PubMedGoogle Scholar
  38. 38.
    Aronson D. Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens. 2003;21:3–12.PubMedGoogle Scholar
  39. 39.
    Asif M, Egan J, Vasan S, et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci U S A. 2000;97:2809–13.PubMedCentralPubMedGoogle Scholar
  40. 40.
    Shapiro BP, Owan TE, Mohammed SF, et al. Advanced glycation end products accumulate in vascular smooth muscle and modify vascular but not ventricular properties in elderly hypertensive canines. Circulation. 2008;118:1002–10.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Dannenberg AL, Levy D, Garrison RJ. Impact of age on echocardiographic left ventricular mass in a healthy population (the Framingham Study). Am J Cardiol. 1989;64:1066–8.PubMedGoogle Scholar
  42. 42.
    Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002;105:1387–93.PubMedGoogle Scholar
  43. 43.
    Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure: Part II: causal mechanisms and treatment. Circulation. 2002;105:1503–8.PubMedGoogle Scholar
  44. 44.
    Iwanaga Y, Aoyama T, Kihara Y, et al. Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats. J Am Coll Cardiol. 2002;39:1384–91.PubMedGoogle Scholar
  45. 45.
    Janicki JS, Brower GL. The role of myocardial fibrillar collagen in ventricular remodeling and function. J Card Fail. 2002;8:S319–325.PubMedGoogle Scholar
  46. 46.
    Baicu CF, Stroud JD, Livesay VA, et al. Changes in extracellular collagen matrix alter myocardial systolic performance. Am J Physiol Heart Circ Physiol. 2003;284:H122–132.PubMedGoogle Scholar
  47. 47.
    Wang J, Hoshijima M, Lam J, et al. Cardiomyopathy associated with microcirculation dysfunction in laminin alpha4 chain-deficient mice. J Biol Chem. 2006;281:213–20.PubMedGoogle Scholar
  48. 48.
    Beltrami CA, Finato N, Rocco M, et al. Structural basis of end-stage failure in ischemic cardiomyopathy in humans. Circulation. 1994;89:151–63.PubMedGoogle Scholar
  49. 49.
    Song Y, Yao Q, Zhu J, Luo B, Liang S. Age-related variation in the interstitial tissues of the cardiac conduction system; and autopsy study of 230 Han Chinese. Forensic Sci Int. 1999;104:133–42.PubMedGoogle Scholar
  50. 50.
    de Jong S, van Veen TA, van Rijen HV, de Bakker JM. Fibrosis and cardiac arrhythmias. J Cardiovasc Pharmacol. 2011;57:630–8.PubMedGoogle Scholar
  51. 51.
    Khan R, Sheppard R. Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology. 2006;118:10–24.PubMedGoogle Scholar
  52. 52.
    Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol. 2007;127:526–37.PubMedGoogle Scholar
  53. 53.
    Hinz B. The myofibroblast: paradigm for a mechanically active cell. J Biomech. 2010;43:146–55.PubMedGoogle Scholar
  54. 54.
    Hinz B, Phan SH, Thannickal VJ, et al. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170:1807–16.PubMedGoogle Scholar
  55. 55.
    Zhao XH, Laschinger C, Arora P, et al. Force activates smooth muscle alpha-actin promoter activity through the Rho signaling pathway. J Cell Sci. 2007;120:1801–9.PubMedGoogle Scholar
  56. 56.
    Ljungqvist A, Unge G. The proliferative activity of the myocardial tissue in various forms of experimental cardiac hypertrophy. Acta Pathol Microbiol Scand A. 1973;81:233–40.PubMedGoogle Scholar
  57. 57.
    Zeisberg EM, Tarnavski O, Zeisberg M, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13:952–61.PubMedGoogle Scholar
  58. 58.
    Humphreys BD, Lin SL, Kobayashi A, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010;176:85–97.PubMedGoogle Scholar
  59. 59.
    van Amerongen MJ, Bou-Gharios G, Popa E, et al. Bone marrow-derived myofibroblasts contribute functionally to scar formation after myocardial infarction. J Pathol. 2008;214:377–86.PubMedGoogle Scholar
  60. 60.
    Kania G, Blyszczuk P, Stein S, et al. Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circ Res. 2009;105:462–70.PubMedGoogle Scholar
  61. 61.
    Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol. 2001;166:7556–62.PubMedGoogle Scholar
  62. 62.
    Haudek SB, Xia Y, Huebener P, et al. Bone marrow-derived fibroblast precursors mediate ischemic cardiomyopathy in mice. Proc Natl Acad Sci U S A. 2006;103:18284–9.PubMedCentralPubMedGoogle Scholar
  63. 63.
    Ghosh AK, Bradham WS, Gleaves LA, et al. Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice: involvement of constitutive transforming growth factor-beta signaling and endothelial-to-mesenchymal transition. Circulation. 2010;122:1200–9.PubMedGoogle Scholar
  64. 64.
    Jankun J, Skrzypczak-Jankun E. Yin and yang of the plasminogen activator inhibitor. Pol Arch Med Wewn. 2009;119:410–7.PubMedGoogle Scholar
  65. 65.
    Moriwaki H, Stempien-Otero A, Kremen M, Cozen AE, Dichek DA. Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type 1 causes cardiac fibrosis in mice. Circ Res. 2004;95:637–44.PubMedGoogle Scholar
  66. 66.
    Cieslik KA, Taffet GE, Carlson S, et al. Immune-inflammatory dysregulation modulates the incidence of progressive fibrosis and diastolic stiffness in the aging heart. J Mol Cell Cardiol. 2011;50:248–56.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Frangogiannis NG, Dewald O, Xia Y, et al. Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. Circulation. 2007;115:584–92.PubMedGoogle Scholar
  68. 68.
    Dewald O, Zymek P, Winkelmann K, et al. CCL2/Monocyte Chemoattractant Protein-1 regulates inflammatory responses critical to healing myocardial infarcts. Circ Res. 2005;96:881–9.PubMedGoogle Scholar
  69. 69.
    Dobaczewski M, Frangogiannis NG. Chemokines and cardiac fibrosis. Front Biosci (Schol Ed). 2009;1:391–405.Google Scholar
  70. 70.
    Frangogiannis NG. Chemokines in the ischemic myocardium: from inflammation to fibrosis. Inflamm Res. 2004;53:585–95.PubMedGoogle Scholar
  71. 71.
    Bujak M, Dobaczewski M, Gonzalez-Quesada C, et al. Induction of the CXC chemokine interferon-{gamma}-inducible protein 10 regulates the reparative response following myocardial infarction. Circ Res. 2009;105:973–83.PubMedCentralPubMedGoogle Scholar
  72. 72.
    Fallon PG, Richardson EJ, McKenzie GJ, McKenzie AN. Schistosome infection of transgenic mice defines distinct and contrasting pathogenic roles for IL-4 and IL-13: IL-13 is a profibrotic agent. J Immunol. 2000;164:2585–91.PubMedGoogle Scholar
  73. 73.
    Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2006;12:99–106.PubMedGoogle Scholar
  74. 74.
    Shearer GM. Th1/Th2 changes in aging. Mech Ageing Dev. 1997;94:1–5.PubMedGoogle Scholar
  75. 75.
    Deng Y, Jing Y, Campbell AE, Gravenstein S. Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol. 2004;172:3437–46.PubMedGoogle Scholar
  76. 76.
    Groban L, Pailes NA, Bennett CD, et al. Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. J Gerontol A Biol Sci Med Sci. 2006;61:28–35.PubMedGoogle Scholar
  77. 77.
    Lakatta EG. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging. Circulation. 2003;107:490–7.PubMedGoogle Scholar
  78. 78.
    Sadoshima J, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. Circ Res. 1993;73:413–23.PubMedGoogle Scholar
  79. 79.
    Rosenkranz S. TGF-beta1 and angiotensin networking in cardiac remodeling. Cardiovasc Res. 2004;63:423–32.PubMedGoogle Scholar
  80. 80.
    Weber KT, Swamynathan SK, Guntaka RV, Sun Y. Angiotensin II and extracellular matrix homeostasis. Int J Biochem Cell Biol. 1999;31:395–403.PubMedGoogle Scholar
  81. 81.
    Basso N, Cini R, Pietrelli A, et al. Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol. 2007;293:H1351–1358.PubMedGoogle Scholar
  82. 82.
    Benigni A, Corna D, Zoja C, et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. 2009;119:524–30.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Billet S, Bardin S, Verp S, et al. Gain-of-function mutant of angiotensin II receptor, type 1A, causes hypertension and cardiovascular fibrosis in mice. J Clin Invest. 2007;117:1914–25.PubMedCentralPubMedGoogle Scholar
  84. 84.
    Stein M, Boulaksil M, Jansen JA, et al. Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin-aldosterone system inhibitors in an aged mouse model. Am J Physiol Heart Circ Physiol. 2010;299:H310–321.PubMedGoogle Scholar
  85. 85.
    Yan L, Vatner DE, O'Connor JP, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007;130:247–58.PubMedGoogle Scholar
  86. 86.
    Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1alpha. Cardiovasc Res. 2008;79:208–17.PubMedGoogle Scholar
  87. 87.
    Sawada M, Carlson JC. Changes in superoxide radical and lipid peroxide formation in the brain, heart and liver during the lifetime of the rat. Mech Ageing Dev. 1987;41:125–37.PubMedGoogle Scholar
  88. 88.
    Schriner SE, Linford NJ, Martin GM, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science. 2005;308:1909–11.PubMedGoogle Scholar
  89. 89.
    Dai DF, Santana LF, Vermulst M, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation. 2009;119:2789–97.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Hafner AV, Dai J, Gomes AP, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging (Albany NY). 2010;2:914–23.Google Scholar
  91. 91.
    Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol. 2001;280:C53–60.PubMedGoogle Scholar
  92. 92.
    Cheng TH, Cheng PY, Shih NL, et al. Involvement of reactive oxygen species in angiotensin II-induced endothelin-1 gene expression in rat cardiac fibroblasts. J Am Coll Cardiol. 2003;42:1845–54.PubMedGoogle Scholar
  93. 93.
    Frangogiannis NG. Chemokines in ischemia and reperfusion. Thromb Haemost. 2007;97:738–47.PubMedGoogle Scholar
  94. 94.
    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.PubMedCentralPubMedGoogle Scholar
  95. 95.
    Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-beta signaling in cardiac remodeling. J Mol Cell Cardiol. 2011;51:600–6.PubMedCentralPubMedGoogle Scholar
  96. 96.
    Biernacka A, Dobaczewski M, Frangogiannis NG. TGF-beta signaling in fibrosis. Growth Factors. 2011;29:196–202.PubMedGoogle Scholar
  97. 97.
    Desmouliere A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122:103–11.PubMedGoogle Scholar
  98. 98.
    Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracellular matrix remodeling and wound healing. J Dermatol Sci. 2004;35:83–92.PubMedGoogle Scholar
  99. 99.
    Mauviel A. Transforming growth factor-beta: a key mediator of fibrosis. Methods Mol Med. 2005;117:69–80.PubMedGoogle Scholar
  100. 100.
    Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.PubMedGoogle Scholar
  101. 101.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84.PubMedGoogle Scholar
  102. 102.
    Rosenkranz S, Flesch M, Amann K, et al. Alterations of beta-adrenergic signaling and cardiac hypertrophy in transgenic mice overexpressing TGF-beta(1). Am J Physiol Heart Circ Physiol. 2002;283:H1253–1262.PubMedGoogle Scholar
  103. 103.
    Brooks WW, Conrad CH. Myocardial fibrosis in transforming growth factor beta(1)heterozygous mice. J Mol Cell Cardiol. 2000;32:187–95.PubMedGoogle Scholar
  104. 104.
    Barcellos-Hoff MH, Dix TA. Redox-mediated activation of latent transforming growth factor-beta 1. Mol Endocrinol. 1996;10:1077–83.PubMedGoogle Scholar
  105. 105.
    Park SK, Kim J, Seomun Y, et al. Hydrogen peroxide is a novel inducer of connective tissue growth factor. Biochem Biophys Res Commun. 2001;284:966–71.PubMedGoogle Scholar
  106. 106.
    Lee AA, Dillmann WH, McCulloch AD, Villarreal FJ. Angiotensin II stimulates the autocrine production of transforming growth factor-beta 1 in adult rat cardiac fibroblasts. J Mol Cell Cardiol. 1995;27:2347–57.PubMedGoogle Scholar
  107. 107.
    Campbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol. 1997;29:1947–58.PubMedGoogle Scholar
  108. 108.
    Ertl G, Frantz S. Healing after myocardial infarction. Cardiovasc Res. 2005;66:22–32.PubMedGoogle Scholar
  109. 109.
    Maggioni AP, Maseri A, Fresco C, et al. Age-related increase in mortality among patients with first myocardial infarctions treated with thrombolysis. The Investigators of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2). N Engl J Med. 1993;329:1442–8.PubMedGoogle Scholar
  110. 110.
    Frangogiannis NG. The immune system and cardiac repair. Pharmacol Res. 2008;58:88–111.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Frangogiannis NG. Matricellular proteins in cardiac adaptation and disease. Physiol Rev. 2012;92:635–88.PubMedGoogle Scholar
  112. 112.
    Frangogiannis NG. The mechanistic basis of infarct healing. Antioxid Redox Signal. 2006;8:1907–39.PubMedGoogle Scholar
  113. 113.
    Bujak M, Kweon HJ, Chatila K, et al. Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol. 2008;51:1384–92.PubMedCentralPubMedGoogle Scholar
  114. 114.
    Swift ME, Burns AL, Gray KL, DiPietro LA. Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol. 2001;117:1027–35.PubMedGoogle Scholar
  115. 115.
    Ding A, Hwang S, Schwab R. Effect of aging on murine macrophages. Diminished response to IFN-gamma for enhanced oxidative metabolism. J Immunol. 1994;153:2146–52.PubMedGoogle Scholar
  116. 116.
    Bujak M, Ren G, Kweon HJ, et al. Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation. 2007;116:2127–38.PubMedGoogle Scholar
  117. 117.
    Shivakumar K, Dostal DE, Boheler K, Baker KM, Lakatta EG. Differential response of cardiac fibroblasts from young adult and senescent rats to ANG II. Am J Physiol Heart Circ Physiol. 2003;284:H1454–1459.PubMedGoogle Scholar
  118. 118.
    Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210.PubMedCentralPubMedGoogle Scholar
  119. 119.
    Jugdutt BI. Aging and remodeling during healing of the wounded heart: current therapies and novel drug targets. Curr Drug Targets. 2008;9:325–44.PubMedGoogle Scholar
  120. 120.
    Jugdutt BI, Jelani A, Palaniyappan A, et al. Aging-related early changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model: effect of early therapy with an angiotensin II type 1 receptor blocker. Circulation. 2010;122:341–51.PubMedGoogle Scholar
  121. 121.
    Jugdutt BI, Jelani A. Aging and defective healing, adverse remodeling, and blunted post-conditioning in the reperfused wounded heart. J Am Coll Cardiol. 2008;51:1399–403.PubMedGoogle Scholar
  122. 122.
    Davis ME, Hsieh PC, Grodzinsky AJ, Lee RT. Custom design of the cardiac microenvironment with biomaterials. Circ Res. 2005;97:8–15.PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Medicine (Cardiolology)Albert Einstein College of MedicineBronxUSA
  2. 2.Department of Medicine (Cardiolology)Albert Einstein College of MedicineBronxUSA

Personalised recommendations