Animal Models of Cardiac Fibrosis

  • Yao Sun
  • Karl T. Weber
Part of the Methods in Molecular Medicine book series (MIMM, volume 117)


A collagen network, composed largely of type I and III fibrillar collagens, is found in the heart’s interstitial space. This network has multiple functions, including the preservation of tissue architecture and chamber geometry. Given its tensile strength, type I collagen is a major determinant of tissue stiffness. Its disproportionate accumulation, expressed in morphological terms as tissue fibrosis, increases myocardial passive and active stiffness and contributes to ventricular diastolic and systolic dysfunction. Various animal models of cardiac fibrosis have been used to study its functional consequences and to elucidate factors regulating the cellular and molecular biology of fibrogenesis. Herein, we present our experience and findings with several models of cardiac fibrosis.

Key Words

Cardiac fibrosis myocardial infarction aldosterone angiotensin II myofibroblasts 



This work was supported in part by National Institutes of Health National Heart, Lung, and Blood Institute grants R01-HL67888 (to Y.S.), and R01-HL62229 (to K.T.W.), and grants from the University of Tennessee Health Science Center Center of Excellence in Connective Tissue Diseases (to Y.S. and K.T.W.).


  1. 1.
    Laurent, G. J. (1987) Dynamic state of collagen: pathways of collagen degradation in vivo and their possible role in regulation of collagen mass. Am. J. Physiol. 252, C1–C9.PubMedGoogle Scholar
  2. 2.
    Docherty, A. J. and Murphy, G. (1990) The tissue metalloproteinase family and the inhibitor TIMP: a study using cDNAs and recombinant proteins. Ann. Rheum. Dis. 49, 469–479.PubMedGoogle Scholar
  3. 3.
    Tyagi, S. C., Ratajska, A. and Weber, K. T. (1993) Myocardial matrix metalloproteinase(s): localization and activation. Mol. Cell. Biochem. 126, 49–59.PubMedCrossRefGoogle Scholar
  4. 4.
    Weber, K. T., Sun, Y. and Katwa, L. C. (1997) Myofibroblasts and local angiotensin II in rat cardiac tissue repair. Int. J. Biochem. Cell Biol. 29, 31–42.PubMedCrossRefGoogle Scholar
  5. 5.
    Jugdutt, B. I. and Amy, R. W. M. (1986) Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J. Am. Coll. Cardiol. 7, 91–102.PubMedCrossRefGoogle Scholar
  6. 6.
    Brilla, C. G., Matsubara, L. S., and Weber, K. T. (1993) Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J. Mol. Cell. Cardiol. 25, 563–575.PubMedCrossRefGoogle Scholar
  7. 7.
    Medugorac, I. (1980) Collagen content in different areas of normal and hypertrophied rat myocardium. Cardiovasc. Res. 14, 551–554.PubMedCrossRefGoogle Scholar
  8. 8.
    Weber, K. T., Pick, R., Janicki, J. S., Gadodia, G., and Lakier, J. B. (1988) Inadequate collagen tethers in dilated cardiopathy. Am. Heart J. 116, 1641–1646.PubMedCrossRefGoogle Scholar
  9. 9.
    Bishop, J., Greenbaum, J., Gibson, D., Yacoub, M., and Laurent, G. J. (1990) Enhanced deposition of predominantly type I collagen in myocardial disease. J. Mol. Cell. Cardiol. 22, 1157–1165.PubMedCrossRefGoogle Scholar
  10. 10.
    Chapman, D., Weber, K. T., and Eghbali, M. (1990) Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in pressure overloaded rat myocardium. Circ. Res. 67, 787–794.PubMedGoogle Scholar
  11. 11.
    Mukherjee, D. and Sen, S. (1990) Collagen phenotypes during development and regression of myocardial hypertrophy in spontaneously hypertensive rats. Circ. Res. 67, 1474–1480.PubMedGoogle Scholar
  12. 12.
    Pfeffer, M. A., Pfeffer, J. M., Fishbein, M. C., Fletcher, P. J., Spadaro, J., Kloner, R. A., and Braunwald, E. (1979) Myocardial infarct size and ventricular function in rats. Circ. Res. 44, 503–512.PubMedGoogle Scholar
  13. 13.
    Sun, Y. and Weber, K. T. (1994) Angiotensin II receptor binding following myocardial infarction in the rat. Cardiovasc. Res. 28, 1623–1628.PubMedCrossRefGoogle Scholar
  14. 14.
    Sun, Y., Zhang, J. Q., Zhang, J., and Lamparter, S. (2000) Cardiac remodeling by fibrous tissue after infarction in rats. J. Lab. Clin. Med. 135, 316–323.PubMedCrossRefGoogle Scholar
  15. 15.
    Sun, Y., Cleutjens, J. P. M., Diaz-Arias, A. A., and Weber, K. T. (1994) Cardiac angiotensin converting enzyme and myocardial fibrosis in the rat. Cardiovasc. Rets. 28, 1423–1432.CrossRefGoogle Scholar
  16. 16.
    Cleutjens, J. P. M., Kandala, J. C., Guarda, E., Guntaka, R. V., and Weber, K. T. (1995) Regulation of collagen degradation in the rat myocardium after infarction. J. Mol. Cell. Cardiol. 27, 1281–1292.PubMedCrossRefGoogle Scholar
  17. 17.
    Peterson, J. T., Li, H., Dillon, L., and Bryant, J. W. (2000) Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Cardiovasc. Res. 46, 307–315.PubMedCrossRefGoogle Scholar
  18. 18.
    Cleutjens, J. P. M., Verluyten, M. J. A., Smits, J. F. M., and Daemen, M. J. A. P. (1995) Collagen remodeling after myocardial infarction in the rat heart. Am. J. Pathol. 147, 325–338.PubMedGoogle Scholar
  19. 19.
    Sun, Y., Zhang, J. Q., Zhang, J., and Ramires, F. J. A. (1998) Angiotensin II, transforming growth factor-β1 and repair in the infarcted heart. J. Mol. Cell. Cardiol. 30, 1559–1569.PubMedCrossRefGoogle Scholar
  20. 20.
    Wei, S., Chow, L. T., Shum, I. O., Qin, L., and Sanderson, J. E. (1999) Left and right ventricular collagen type I/III ratios and remodeling post-myocardial infarction. J. Cardiac Failure 5, 117–126.CrossRefGoogle Scholar
  21. 21.
    Gideon, P. A., Warrington, K. J., Lu, L., Sun, Y., and Weber, K. T. (2003) Autoimmune lymphocyte response at sites remote to myocardial infarction [abstract]. Circulation 108, IV–69.Google Scholar
  22. 22.
    Sun, Y. and Weber, K. T. (1996) Angiotensin converting enzyme and myofibroblasts during tissue repair in the rat heart. J. Mol. Cell. Cardiol. 28, 851–858.PubMedCrossRefGoogle Scholar
  23. 23.
    Blankesteijn, W. M., Essers-Janssen, Y. P. G., Verluyten, M. J. A., Daemen, M. J. A. P., and Smits, J. F. M. (1997) A homologue of Drosophila tissue polarity gene frizzled is expressed in migrating myofibroblasts in the infarcted rat heart. Nat. Med. 3, 541–544.PubMedCrossRefGoogle Scholar
  24. 24.
    Peterson, D. J., Ju, H., Hao, J., Panagia, M., Chapman, D. C., and Dixon, I. M. (1999) Expression of Gi-2α and G in myofibroblasts localized to the infarct scar in heart failure due to myocardial infarction. Cardiovasc. Res. 41, 575–585.PubMedCrossRefGoogle Scholar
  25. 25.
    Gabbiani, G., Hirschel, B. J., Ryan, G. B., Statkov, P. R., and Majno, G. (1972) Granulation tissue as a contractile organ. A study of structure and function. J. Exp. Med. 135, 719–734.PubMedCrossRefGoogle Scholar
  26. 26.
    Yokozeki, M., Moriyama, K., Shimokawa, H., and Kuroda, T. (1997) Transforming growth factor-β1 modulates myofibroblastic phenotype of rat palatal fibroblasts in vitro. Exp. Cell Res. 231, 328–336.PubMedCrossRefGoogle Scholar
  27. 27.
    Khouw, I. M., van Wachem, P. B., Plantinga, J. A., Vujaskovic, Z., Wissink, M. J., de Leij, L. F., and van Luyn, M. J. (1999) TGF-β and βFGF affect the differentiation of proliferating porcine fibroblasts into myofibroblasts in vitro. Biomaterials 20, 1815–1822.PubMedCrossRefGoogle Scholar
  28. 28.
    Evans, R. A., Tian, Y. C., Steadman, R., and Phillips, A. O. (2003) TGF-β1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins. Exp. Cell Res. 282, 90–100.PubMedCrossRefGoogle Scholar
  29. 29.
    Willems, I. E. M. G., Havenith, M. G., De Mey, J. G. R., and Daemen, M. J. A. P. (1994) The α-smooth muscle actin-positive cells in healing human myocardial scars. Am. J. Pathol. 145, 868–875.PubMedGoogle Scholar
  30. 30.
    Sun, Y., Zhang, J., Zhang, J. Q., and Ramires, F. J. A. (2000) Local angiotensin II and transforming growth factor-β1 in renal fibrosis of rats. Hypertension 35, 1078–1084.PubMedGoogle Scholar
  31. 31.
    Ou, R., Sun, Y., Ganjam, V. K., and Weber, K. T. (1996) In situ production of angiotensin II by fibrosed rat pericardium. J. Mol. Cell. Cardiol. 28, 1319–1327.PubMedCrossRefGoogle Scholar
  32. 32.
    Yamagishi, H., Kim, S., Nishikimi, T., Takeuchi, K., and Takeda, T. (1993) Contribution of cardiac renin-angiotensin system to ventricular remodelling in myocardial-infarcted rats. J. Mol. Cell. Cardiol. 25, 1369–1380.PubMedCrossRefGoogle Scholar
  33. 33.
    Jugdutt, B. I., Humen, D. P., Khan, M. I., and Schwarz-Michorowski, B. L. (1992) Effect of left ventricular unloading with captopril on remodeling and function during healing of anterior transmural myocardial infarction in the dog. Can. J. Cardiol. 8, 151–163.PubMedGoogle Scholar
  34. 34.
    Jugdutt, B. I., Khan, M. I., Jugdutt, S. J., and Blinston, G. E. (1995) Effect of enalapril on ventricular remodeling and function during healing after anterior myocardial infarction in the dog. Circulation 91, 802–812.PubMedGoogle Scholar
  35. 35.
    Michel, J.-B., Lattion, A.-L., Salzmann, J.-L., Cerol, M. L., Philippe, M., Camilleri, J.-P., and Corvol, P. (1988) Hormonal and cardiac effects of converting enzyme inhibition in rat myocardial infarction. Circ. Res. 62, 641–650.PubMedGoogle Scholar
  36. 36.
    van Krimpen, C., Schoemaker, R. G., Cleutjens, J. P. M., Smits, J. F. M., Struyker-Boudier, H. A. J., Bosman, F. T., and Daemen, M. J. A. P. (1991) Angiotensin I converting enzyme inhibitors and cardiac remodeling. Basic Res. Cardiol. 86, 149–155.PubMedGoogle Scholar
  37. 37.
    Smits, J. F. M., van Krimpen, C., Schoemaker, R. G., Cleutjens, J. P. M., and Daemen, M. J. A. P. (1992) Angiotensin II receptor blockade after myocardial infarction in rats: effects on hemodynamics, myocardial DNA synthesis, and interstitial collagen content. J. Cardiovasc. Pharmacol. 20, 772–778.PubMedGoogle Scholar
  38. 38.
    Hodsman, G. P., Kohzuki, M., Howes, L. G., Sumithran, E., Tsunoda, K., and Johnston, C. I. (1988) Neurohumoral responses to chronic myocardial infarction in rats. Circulation 78, 376–381.PubMedGoogle Scholar
  39. 39.
    Hirsch, A. T., Talsness, C. E., Schunkert, H., Paul, M., and Dzau, V. J. (1991) Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ. Res. 69, 475–482.PubMedGoogle Scholar
  40. 40.
    Sun, Y., Ratajska, A., Zhou, G., and Weber, K. T. (1993) Angiotensin converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone. J. Lab. Clin. Med. 122, 395–403.PubMedGoogle Scholar
  41. 41.
    Young, M., Fullerton, M., Dilley, R., and Funder, J. (1994) Mineralocorticoids, hypertension, and cardiac fibrosis. J. Clin. Invest. 93, 2578–2583.PubMedCrossRefGoogle Scholar
  42. 42.
    Sun, Y., Ramires, F. J. A., and Weber, K. T. (1997) Fibrosis of atria and great vessels in response to angiotensin II or aldosterone infusion. Cardiovasc. Res. 35, 138–147.PubMedCrossRefGoogle Scholar
  43. 43.
    Campbell, S. E., Janicki, J. S., and Weber, K. T. (1995) Temporal differences in fibroblast proliferation and phenotype expression in response to chronic administration of angiotensin II or aldosterone. J. Mol. Cell. Cardiol. 27, 1545–1560.PubMedCrossRefGoogle Scholar
  44. 44.
    Sun, Y., Zhang, J., Lu, L., Chen, S. S., Quinn, M. T., and Weber, K. T. (2002) Aldosterone-induced inflammation in the rat heart. iRole of oxidative stress. Am. J. Pathol. 161, 1773–1781.PubMedCrossRefGoogle Scholar
  45. 45.
    Ahokas, R. A., Warrington, K. J., Gerling, I. C., et al. (2003) Aldosteronism and peripheral blood mononuclear cell activation. A neuroendocrine-immune interface. Circ. Res. 93, e124–e135.PubMedCrossRefGoogle Scholar
  46. 46.
    Gerling, I. C., Sun, Y., Ahokas, R. A., Wodi, L. A., et al. (2003) Aldosteronism: an immunostimulatory state precedes the proinflammatory/fibrogenic cardiac phenotype. Am. J. Physiol. Heart Circ. Physiol. 285, H813–H821.PubMedGoogle Scholar
  47. 47.
    Rousseau-Plasse, A., Lenfant, M., and Potier, P. (1996) Catabolism of the hemoregulatory peptide N-Acetyl-Ser-Asp-Lys-Pro: a new insight into the physiological role of the angiotensin-I-converting enzyme N-active site. Bioorg. Med. Chem. 4, 1113–1119.PubMedCrossRefGoogle Scholar
  48. 48.
    Sun, Y., Zhang, J., Lu, L., Bedigian, M. P., Robinson, A. D., and Weber, K. T. (2004)Tissue angiotensin II in the regulation of inflammatory and fibrogenic components of repair in the rat heart. J. Lab. Clin. Med., in press.Google Scholar
  49. 49.
    Robert, V., Heymes, C., Silvestre, J.-S., Sabri, A., Swynghedauw, B., and Delcayre, C. (1999) Angiotensin AT1 receptor subtype as a cardiac target of aldosterone. Role in aldosterone-salt-induced fibrosis. Hypertension 33, 981–986.Google Scholar
  50. 50.
    Tan, L. B., Jalil, J. E., Pick, R., Janicki, J. S., and Weber, K. T. (1991) Cardiac myocyte necrosis induced by angiotensin II. Circ. Res. 69, 1185–1195.PubMedGoogle Scholar
  51. 51.
    Sun, Y., Ratajska, A., and Weber, K. T. (1995) Inhibition of angiotensin-converting enzyme and attenuation of myocardial fibrosis by lisinopril in rats receiving angiotensin II. J. Lab. Clin. Med. 126, 95–101.PubMedGoogle Scholar
  52. 52.
    Brilla, C. G., Pick, R., Tan, L. B., Janicki, J. S., and Weber, K. T. (1990) Remodeling of the rat right and left ventricle in experimental hypertension. Circ. Res. 67, 1355–1364.PubMedGoogle Scholar
  53. 53.
    Everett, A. D., Tufro-McReddie, A., Fisher, A., and Gomez, R. A. (1994) Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-β1 expression. Hypertension 23, 587–592.PubMedGoogle Scholar
  54. 54.
    Rupérez, M., Ruiz-Ortega, M., Esteban, V., Lorenzo, O., Mezzano, S., Plaza, J. J., and Egido, J. ((2003) Angiotensin II increases connective tissue growth factor in the kidney. Am. J. Pathol. 163, 1937–1947.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang, H. D., Xu, S., Johns, D. G., Du, Y., Quinn, M. T., Cayatte, A. J., and Cohen, R. A. (2001) Role of NADPH oxidase in the vascular hypertrophic and oxidative stress response to angiotensin II in mice. Circ. Res. 88, 947–953.PubMedCrossRefGoogle Scholar
  56. 56.
    Harrison, D. G., Cai, H., Landmesser, U., and Griendling, K. K. (2003) Interactions of angiotensin II with NAD(P)H oxidase, oxidant stress and cardiovascular disease. J. Renin Angiotensin Aldosterone Syst. 4, 51–61.PubMedCrossRefGoogle Scholar
  57. 57.
    Barnes, P. J. and Karin, M. (1997) Nuclear factor-κB: a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071.PubMedCrossRefGoogle Scholar
  58. 58.
    Muller, D. N., Dechend, R., Mervaala, E. M., et al. (2000) NF-κB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. Hypertension 35, 193–201.PubMedGoogle Scholar
  59. 59.
    Lijnen, P. J., Petrov, V. V., and Fagard, R. H. (2001) Angiotensin II-induced stimulation of collagen secretion and production in cardiac fibroblasts is mediated via angiotensin II subtype 1 receptors. J. Renin Angiotensin Aldosterone Syst. 2, 117–122.PubMedGoogle Scholar
  60. 60.
    Lijnen, P. J. and Petrov, V. V. (2003) Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling. Methods Find. Exp. Clin. Pharmacol. 25, 541–564.PubMedCrossRefGoogle Scholar
  61. 61.
    Sun, Y. and Weber, K. T. (1996) Angiotensin-converting enzyme and wound healing in diverse tissues of the rat. J. Lab. Clin. Med. 127, 94–101.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  • Yao Sun
    • 1
  • Karl T. Weber
    • 1
  1. 1.Division of Cardiovascular Diseases, Department of MedicineUniversity of Tennessee Health Science CenterMemphis

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