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. 2007 May 1;9(3):704–713. doi: 10.1111/j.1582-4934.2005.tb00501.x

Early induction of matrix metalloproteinase‐9 transduces signaling in human heart end stage failure

Karni S Moshal 1, Neetu Tyagi 1, Valerie Moss 1, Brooke Henderson 1, Mesia Steed 1, Alexander Ovechkin 1, Giorgio M Aru 2, Suresh C Tyagi 1,✉
PMCID: PMC6741634  PMID: 16202218

Abstract

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic‐MMP‐2 and ‐9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP‐2 and ‐9 in ailing to failing myocardium. Activation of MMP‐2 and ‐9 leads to induction of proteinase activated receptor‐1 (PAR‐1). We hypothesize that the early induction of MMP‐9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase‐1 (ERK‐1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP‐2 and ‐9 gelatinolytic activities was made by real‐time quantitative zymography. Gel phosphorylation staining for PAR‐1 showed a significant increase in ICM hearts. Western blot and RT‐PCR analysis and in‐situ labeling, showed significant increased expression of PAR‐1, ERK‐1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP‐9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end‐stage human heart failure.

Keywords: real time zymography, PAR‐1, ERK‐1 FAK, capillaries, phosphorylation, kinase, endothelial myocyte coupling, cardiac synchronization

References

  • 1. Brilla CG, Rupp H. Myocardial collagen matrix remodeling and congestive heart failure. Cardiologia 1994; 39: 389–93. [PubMed] [Google Scholar]
  • 2. Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cigola E, Quaini F, Sonnenblick EH, Olivetti G, Anversa P. Structural basis of end‐stage failure in ischemic cardiomyopathy in humans. Circulation 1994; 89: 151–63. [DOI] [PubMed] [Google Scholar]
  • 3. Factor SM. Role of extracellular matrix in dilated cardiomyopathy. Heart Fail. 1994; 9: 260–8. [Google Scholar]
  • 4. Alexander CM, Werb Z. Proteinases and extracellular matrix remodeling. Curr Opin Cell Biol. 1989; 1: 974–82. [DOI] [PubMed] [Google Scholar]
  • 5. Khohka R, Denhardt DT. Matrix metaloproteinases and tissue inhibitors of metalloproteinases: a review of their role in tumorigenesis and tissue invasion. Invasion Metastasis 1989; 9: 391–405. [PubMed] [Google Scholar]
  • 6. Dano K, Andreason PA Grondahl‐Hansen J, Kristensen P, Nielsen LS, Skriver L. Plasminogen activators, tissue degradation and cancer. Adv Cancer Res 1985; 44: 139–266. [DOI] [PubMed] [Google Scholar]
  • 7. Mignatti P, Robbins E, Rifkin DB. Tumor invasion through human amniotic membrane: requirement for a proteinase cascade. Cell 1986; 47: 487–98. [DOI] [PubMed] [Google Scholar]
  • 8. Liotta LA, Steeg PS, Stetler‐Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991; 64:327–36. [DOI] [PubMed] [Google Scholar]
  • 9. Harper E, Blotch KJ, Gross J. The zymogen of tadpole collagenase. Biochemistry 1971; 10: 3035–41. [DOI] [PubMed] [Google Scholar]
  • 10. Vaes G. A latent collagenase by bone and skin explant in culture. Biochem J 1971; 123: 23–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Tyagi SC, Ratzaska A, Weber KT. Myocardial matrix metalloproteinase: activation and localization. Mol Cell Biochem. 1993; 126: 49–59. [DOI] [PubMed] [Google Scholar]
  • 12. Tyagi SC, Kumar SG, Glover G. Induction of tissue inhibitor and matrix metalloproteinases by serum in human‐heart derived fibroblast and endomyocardial endothelial cells. J Cell Biochem 1995; 58: 360–72. [DOI] [PubMed] [Google Scholar]
  • 13. Hunt MJ, Aru GM, Hayden MR, Moore CK, Hoit BD, Tyagi SC. Induction of oxidative stress and disintegrin metallo proteinase in human heart end stage failure. Am J Lung Cell Cell Mol Physiol 2002; 283: L239–45. [DOI] [PubMed] [Google Scholar]
  • 14. Tyagi SC, Campbell SE, Reddy HK, Tjahja E, Voelker DJ. Matrix metalloproteinase activity expression in infracted, non‐infracted and dilated cardiomyopathic human hearts. Mol Cell Biochem 1996; 155: 13–21. [DOI] [PubMed] [Google Scholar]
  • 15. Tyagi SC, Kumar SG, Haas SJ, Reddy HK, Voelker DJ, Hayden MR, Demmy TL, Schmaltz RA, Curtis JJ. Post‐transcriptional regulation of extracellular matrix metalloproteinase in human heart end stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol. 1996; 28: 1415–28. [DOI] [PubMed] [Google Scholar]
  • 16. Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley AJ III, Spinale FG. Increased matrix metalloproteinase activity and selective up‐regulation in LV myocardium from patients with end‐stage dilated cardiomyopathy. Circulation 1998; 97: 1708–15. [DOI] [PubMed] [Google Scholar]
  • 17. Li YY, Feldman AM, Sun Y, McTiernan CF. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 1998; 98: 1728–34. [DOI] [PubMed] [Google Scholar]
  • 18. Mann DL, Spinale FG. Activation of matrix metallo proteinases in the failing human heart: breaking the tie that binds. Circulation 1998; 98: 1699–1702. [DOI] [PubMed] [Google Scholar]
  • 19. Coker ML, Thomas CV, Clair MJ, Hendrick JW, Krombach RS, Galis ZS, Spinale FG. Myocardial matrix metallo proteinase activity and abundance with congestive heart failure. Am J Physiol. 1998; 274: H1516–23. [DOI] [PubMed] [Google Scholar]
  • 20. Spinale FG, Coker ML, Thomas CV, Walker JD, Mukherjee R, Hebbar L. Time‐dependent changes in matrix metalloproteinase activity and expression during the progression of congestive heart failure: relation to ventricular and myocyte function. Circ Res. 1998; 82: 482–95. [DOI] [PubMed] [Google Scholar]
  • 21. Kawabata A, Kuroda R. Protease‐activated receptor (PAR), novel family of G protein‐coupled seven transmembrane domain receptors: activation mechanisms and physiological roles. Jpn J Pharmacol. 2000; 82: 171–4. [DOI] [PubMed] [Google Scholar]
  • 22. Cox MJ, Hawkins UA, Hoit BD, Tyagi SC. Attenuation of oxidative stress and remodeling by cardiac inhibitor of metalloproteinase protein transfer. Circulation 2004; 109: 2123–8. [DOI] [PubMed] [Google Scholar]
  • 23. Moshal KS, Tyagi N, Henderson B, Ovechkin AV, Tyagi SC. Protease activated receptor and endothelial‐myocyte uncoupling in chronic heart failure. Am J Physiol Heart Circ Physiol. 2005; 288: H2770–7. [DOI] [PubMed] [Google Scholar]
  • 24. Tyagi SC, Matsubara L, Weber KT. Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of the rat myocardium and uterus. Clin Biochem. 1993; 26: 191–8. [DOI] [PubMed] [Google Scholar]
  • 25. Hattori S, Fujisaki H, Kiriyama T, Yokoyama T, Irie S. Real‐time zymography and reverse zymography: a method for decting activities of MMP and their inhibitors using FITC‐labeled collagen and casein as substrates. Anal Biochem. 2002; 301: 27–34. [DOI] [PubMed] [Google Scholar]
  • 26. Deschamps AM, Apple KA, Leonardi AH, McLean JE, Yarbrough WM, Stroud RE, Clark LL, Sample JA, Spinale FG. Myocardial interstitial MMP activity is altered by mechanical changes in LV load interaction with the angiotensin type 1 receptor. Cir Res. 2005; 96: 1110–8. [DOI] [PubMed] [Google Scholar]
  • 27. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein‐dye binding. Anal Biochem. 1976; 72: 248–54. [DOI] [PubMed] [Google Scholar]
  • 28. Brower GL, Janicki JS. Contribution of ventricular remodeling to pathogenesis of heart failure in rats. Am J Physiol. 2001; 280: H674–83. [DOI] [PubMed] [Google Scholar]
  • 29. Bendeck MP, Zempo N, Clowes AW, Galardy RE, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Cir Res. 1994; 75: 539–45. [DOI] [PubMed] [Google Scholar]
  • 30. Ducharme A, Frantz S, Aikawa M, Rabkin E, Lindsey M, Rohde LE, Schoen FJ, Kelly RA, Werb Z, Libby P, Lee RT. Targeted deletion of MMP‐9 attenuates left ventricular enlargement and collagen accumulation after experimental myocardial infraction. J Clin Invest. 2000; 106: 55–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Damiano BP, Cheung WM, Santulli RJ, Fung‐Leung WP, Ngo K, Ye RD, Darrow AL, Derian CK, de Garavilla L, Andrade‐Gordon P. Cardiovascular responses mediated by protease‐activated receptor‐2 (PAR‐2) and thrombin receptor (PAR‐1) are distinguished in mice deficient in PAR‐2 or PAR‐1. J Pharmacol Exp Ther. 1999; 288: 671–8. [PubMed] [Google Scholar]
  • 32. Cho A, Graves J, Reidy AM. Mitogen‐activated protein kinases mediated matrix metalloproteinase‐9 expression in vascular smooth muscle cells. Arterioscler Thromb Vas Biol. 2000; 20: 2527–32. [DOI] [PubMed] [Google Scholar]
  • 33. Sabri A, Muske G, Zhang H, Pak E, Darrow A, Andrade‐Gordon P, Steinberg SF. Signaling properties and functions of two distinct cardiomyocyte protease activated receptors. Circ Res. 2000; 86: 1054–61. [DOI] [PubMed] [Google Scholar]
  • 34. Riza Erbay A, Turhan H, Aksoy Y, Senen K, Yetkin E. Activation of coagulation system in dilated cardiomyopathy: comparison of patients with and without left ventricular thrombus. Coron Artery Dis. 2004; 15: 265–8. [DOI] [PubMed] [Google Scholar]
  • 35. Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K. The coagulation system is activated in idiopathic cardiomyopathy. J Am Coll Cardiol. 1995; 26: 1757–8. [DOI] [PubMed] [Google Scholar]

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