Abstract
Regulation of the extracellular matrix (ECM) is an important therapeutic target that can potentially attenuate the adverse ventricular remodeling seen in the progression of heart failure. Matrix metalloproteinases (MMPs) degrade numerous ECM proteins. Importantly, the activation of MMPs and their endogenous inhibitors (TIMPs) are associated with ventricular remodeling. Bioactive-molecules (vasoactive peptides) become activated in proportion to the magnitude of heart failure and have been demonstrated to affect directly collagen degradation as well as collagen synthesis in the myocardium. Pro-fibrotic factors such as norepinephrine, angiotensin II, and endothelin-1 stimulate fibrosis by modulating collagen synthesis and MMP/TIMP activity. Antagonism of these bioactive-molecules has produced improved hemodynamic performance concomitant with modulation of MMP/TIMP activity and in association with reverse remodeling. The natriuretic peptides and nitric oxide, both of which function via the second messenger cGMP, demonstrate anti-fibrotic actions by inhibiting collagen synthesis and by stimulating MMP activity. Furthermore, bioactive-molecules along with certain cytokines are reported to amplify MMP activity, suggesting that different signaling systems work together to modulate ECM turnover. Taken together, the evidence supports an important functional role for bioactive-molecules in the regulation of ECM turnover and suggests that pharmacological intervention at the level of such bioactive molecules may provide potential therapeutic strategies for attenuation of the adverse ventricular remodeling associated with the progression of heart failure.
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References
Spinale FG. Matrix metalloproteinases: Regulation and dysregulation in the failing heart. Circ Res 2002;90:520–530.
Woessner JF, Jr. The matrix metalloproteinase family. In: Parks WC, Mecham RP, eds. Matrix Metalloproteinases. San Diego, CA: Academic Press, 1998:1–14.
Laviades C, Varo N, Fernandez J, Mayor G, Gil MJ, Monreal I, Diez J. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998;98:535–540.
Li-Saw-Hee FL, Edmunds E, Blann AD, Beevers DG, Lip GY. Matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 levels in essential hypertension. Relationship to left ventricular mass and anti-hypertensive therapy. Int J Cardiol 2000;75:43–47.
Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley AJ 3rd, Spinale FG. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 1998;97:1708–1715.
Armstrong PW, Moe GW, Howard RJ, Grima EA, Cruz TF. Structural remodelling in heart failure: Gelatinase induction. Can J Cardiol 1994;10:214–220.
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;82:482–495.
Li YY, Feldman AM, Sun Y, McTiernan CF. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation 1998;98:1728–1734.
Fedak PW, Altamentova SM, Weisel RD, Nili N, Ohno N, Verma S, Lee TY, Kiani C, Mickle DA, Strauss BH, Li RK. Matrix remodeling in experimental and human heart failure: A possible regulatory role for TIMP-3. Am J Physiol Heart Circ Physiol 2003;284:H626–H634.
Peterson JT, Li H, Dillon L, Bryant JW. Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Cardiovasc Res 2000;46:307–315.
Willenbrock R, Philipp S, Mitrovic V, Dietz R. Neurohumoral blockade in CHF management. J Renin Angiotensin Aldosterone Syst 2000;1(Suppl 1):24–30.
Chen HH, Burnett JC. Natriuretic peptides in the pathophysiology of congestive heart failure. Curr Cardiol Rep 2000;2:198–205.
Luo JD, Xie F, Zhang WW, Ma XD, Guan JX, Chen X. Simvastatin inhibits noradrenaline-induced hypertrophy of cultured neonatal rat cardiomyocytes. Br J Pharmacol 2001;132:159–164.
Akiyama-Uchida Y, Ashizawa N, Ohtsuru A, Seto S, Tsukazaki T, Kikuchi H, Yamashita S, Yano K. Norepinephrine enhances fibrosis mediated by TGF-ß in cardiac fibroblasts. Hypertension 2002;40:148–154.
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;73:413–423.
Eble DM, Strait JB, Govindarajan G, Lou J, Byron KL, Samarel AM. Endothelin-induced cardiac myocyte hypertrophy: Role for focal adhesion kinase. Am J Physiol Heart Circ Physiol 2000;278:H1695–H1707.
Piacentini L, Gray M, Honbo NY, Chentoufi J, Bergman M, Karliner JS. Endothelin-1 stimulates cardiac fibroblast proliferation through activation of protein kinase C. J Mol Cell Cardiol 2000;32:565–576.
Calderone A, Thaik CM, Takahashi N, Chang DL, Colucci WS. Nitric oxide, atrial natriuretic peptide, and cyclic GMP inhibit the growth-promoting effects of norepinephrine in cardiac myocytes and fibroblasts. J Clin Invest 1998;101:812–818.
Katz AM. The hemodynamic defense reaction. In: Katz AM, eds. Heart Failure. Pathology,Molecular Biology, and Clinical Management. Philadelphia, PA: Lippincott Williams& Wilkins; 2000:109–154.
Cameron VA, Rademaker MT, Ellmers LJ, Espiner EA, Nicholls MG, Richards AM. Atrial (ANP) and brain natriuretic peptide (BNP) expression after myocardial infarction in sheep: ANP is synthesized by fibroblasts infiltrating the infarct. Endocrinology 2000;141:4690–4697.
Tsuruda T, Boerrigter G, Huntley BK, Noser JA, Cataliotti A, Costello-Boerrigter LC, Chen HH, Burnett JC, Jr. Brain natriuretic peptide is produced in cardiac fibroblasts and induces matrix metalloproteinases. Circ Res 2002;91:1127–1134.
Horio T, Tokudome T, Maki T, Yoshihara F, Suga S-I, Nishikimi T, Kojima M, Kawano Y, Kangawa K. Gene expression, secretion, and autocrine action of C-type natriuretic peptide in cultured adult rat cadiac fibroblasts. Endocrinologyl 2003;144:2279–2284.
Koller KJ, Goeddel DV. Molecular biology of the natriuretic peptides and their receptors. Circulation 1992;86:1081–1088.
Lin X, H¨anze, J, Heese, F, Sodmann, R, Lang RE. Gene expression of natriuretic peptide receptors in myocardial cells. Circ Res 1995;77:750–758.
Kupfahl C, Pink D, Friedrich K, Zurbrugg HR, Neuss M, Warnecke C, Fielitz J, Graf K, Fleck E, Regitz-Zagrosek V. Angiotensin II directly increases transforming growth factor beta1 and osteopontin and indirectly affects collagen mRNA expression in the human heart. Cardiovasc Res 2000;46:463–475.
Schultz Jel J, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, Nix SL, Kimball TR, Doetschman T. TGF-ß1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 2002;109:787–796.
Guarda E, Katwa LC, Myers PR, Tyagi SC, Weber KT. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc Res 1993;27:2130–2134.
Briest W, Holzl A, Rassler B, Deten A, Leicht M, Baba HA, Zimmer HG. Cardiac remodeling after long term norepinephrine treatment in rats. Cardiovasc Res 2001;52:265–273.
Dostal DE. Regulation of cardiac collagen. Angiotensin and cross-talk with local growth factors. Hypertension 2001;37:841–844.
Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation: What is all the fuss about? Matrix Biol 1997;15:519–526.
Bond M, Chase AJ, Baker AH, Newby AC. Inhibition of transcription factor NF-κ reduces matrix metalloproteinase-1,-3 and-9 production by vascular smooth muscle cells. Cardiovasc Res 2001;50:556–565.
Bergman MR, Cheng S, Honbo N, Piacentini L, Karliner JS, Lovett DH. A functional activating protein 1 (AP-1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and JunB-FosB heterodimers. Biochem J 2003;369:485–496.
Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463–516.
Rossi MA, Peres LC. Effect of captopril on the prevention and regression of myocardial cell hypertrophy and interstitial fibrosis in pressure overload cardiac hypertrophy. Am Heart J 1992;124:700–709.
Brilla CG, Zhou G, Matsubara L, Weber KT. Collagen metabolism in cultured adult rat cardiac fibroblasts: Response to angiotensin II and aldosterone. J Mol Cell Cardiol 1994;26:809–820.
Chua CC, Hamdy RC, Chua BH. Angiotensin II induces TIMP-1 production in rat heart endothelial cells. Biochim Biophys Acta 1996;1311:175–180.
Varo N, Iraburu MJ, Varela M, Lopez B, Etayo JC, Diez J. Chronic AT1 blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats. Hypertension 2000;35:1197–1202.
Coker ML, Jolly JR, Joffs C, Etoh T, Holder JR, Bond BR, Spinale FG. Matrix metalloproteinase expression and activity in isolated myocytes after neurohormonal stimulation. Am J Physiol Heart Circ Physiol 2001;281:H543–H551.
Rouet-Benzineb P, Gontero B, Dreyfus P, Lafuma C. Angiotensin II induces nuclear factor-□B activation in cultured neonatal rat cardiomyocytes through protein kinase C signaling pathway. J Mol Cell Cardiol 2000;32:1767–1778.
McElmurray JH 3rd, Mukherjee R, New RB, Sampson AC, King MK, Hendrick JW, Goldberg A, Peterson TJ, Hallak H, Zile MR, Spinale FG. Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: Comparative effects on left ventricular function and geometry. J Pharmacol Exp Ther 1999;291:799–811.
Reinhardt D, Sigusch HH, Hensse J, Tyagi SC, Korfer R, Figulla HR. Cardiac remodeling in end stage heart failure: Upregulation of matrix metalloproteinase (MMP) irrespective of the underlying disease, and evidence for a direct inhibitory effect of ACE inhibitors on MMP. Heart 2002;88:525–530.
Masutomo K, Makino N, Fushiki MS. Effects of losartan on the collagen degradative enzymes in hypertrophic and congestive types of cardiomyopathic hamsters. Mol Cell Biochem 2001;224:19–27.
Papakonstantinou E, Roth M, Kokkas B, Papadopoulos C, Karakiulakis G. Losartan inhibits the angiotensin II-induced modifications on fibrinolysis and matrix deposition by primary human vascular smooth muscle cells. J Cardiovasc Pharmacol 2001;38:715–728.
Peng J, Gurantz D, Tran V, Cowling RT, Greenberg BH. Tumor necrosis factor-α-induced AT1 receptor upregulation enhances angiotensin II-mediated cardiac fibroblast responses that favor fibrosis. Circ Res 2002;91:1119–1126.
Gray MO, Long CS, Kalinyak JE, Li HT, Karliner JS. Angiotensin II stimulates cardiac myocyte hypertrophy via paracrine release of TGF-ß1 and endothelin-1 from fibroblasts. Cardiovasc Res 1998;40:352–363.
Fujisaki H, Ito H, Hirata Y, Tanaka M, Hata M, Lin M, Adachi S, Akimoto H, Marumo F, Hiroe M. Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. J Clin Invest 1995;96:1059–1065.
Guarda E, Katwa LC, Myers PR, Tyagi SC, Weber KT. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc Res 1993;27:2130–2134.
Xu S, Denton CP, Holmes A, Dashwood MR, Abraham DJ, Black CM. Endothelins: Effect on matrix biosynthesis and proliferation in normal and scleroderma fibroblasts. J Cardiovasc Pharmacol 1998;31:S360–S363.
Yao J, Morioka T, Li B, Oite T. Endothelin is a potent inhibitor of matrix metalloproteinase-2 secretion and activation in rat mesangial cells. Am J Physiol Renal Physiol 2001;280:F628–F635.
Kitamura A, Kagami S, Urushihara M, Kondo S, Yoshizumi M, Tamaki T, Kuroda Y. Endothelin-1 is a potent stimulator of α1β1 integrin-mediated collagen matrix remodeling by rat mesangial cells. Biochem Biophys Res Commun 2002;299:555–561.
Rosano L, Varmi M, Salani D, Di Castro V, Spinella F, Natali PG, Bagnato A. Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Cancer Res 2001;61:8340–8346.
Ammarguellat FZ, Gannon PO, Amiri F, Schiffrin EL. Fibrosis, matrix metalloproteinases, and inflammation in the heart of DOCA-salt hypertensive rats: Role of ETA receptors. Hypertension 2002;39:679–684.
Fernandez-Patron C, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2 cleaves big endothelin-1 yielding a novel vasoconstrictor. Circ Res 1999;85:906–911.
Schmidt BM, Schmieder RE. Aldosterone-induced cardiac damage: Focus on blood pressure independent effects. Am J Hypertens 2003;16:80–86.
Stockand JD, Meszaros JG. Aldosterone stimulates proliferation of cardiac fibroblasts by activating Ki-RasA and MAPK1/2 signaling. Am J Physiol Heart Circ Physiol 2003;284:H176–H184.
Lijnen P, Petrov V. Induction of cardiac fibrosis by aldosterone. J Mol Cell Cardiol 2000;32:865–879.
Brilla CG, Weber KT. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 1992;120:893–901.
Kohler E, Bertschin S, Woodtli T, Resink T, Erne P. Does aldosterone-induced cardiac fibrosis involve direct effects on cardiac fibroblasts? J Vasc Res 1996;33:315–326.
Rombouts K, Wielant A, Hellemans K, Schuppan D, Geerts A. Influence of aldosterone on collagen synthesis and proliferation of rat cardiac fibroblasts. Br J Pharmacol 2001;134:224–232.
Suzuki G, Morita H, Mishima T, Sharov VG, Todor A, Tanhehco EJ, Rudolph AE, McMahon EG, Goldstein S, Sabbah HN. Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure. Circulation 2002;106:2967–2972.
Briest W, Holzl A, Rassler B, Deten A, Leicht M, Baba HA, Zimmer HG. Cardiac remodeling after long term norepinephrine treatment in rats. Cardiovasc Res 2001;52:265–273.
Senzaki H, Paolocci N, Gluzband YA, Lindsey ML, Janicki JS, Crow MT, Kass DA. □-blockade prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction. Circ Res 2000;86:807–815.
Maki T, Horio T, Yoshihara F, Suga S, Takeo S, Matsuo H, Kangawa K. Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts. Br J Pharmacol 2000;131:1204–1210.
Baldini PM, De Vito P, Fraziano M, Mattioli P, Luly P, Di Nardo P. Atrial natriuretic factor inhibits mitogeninduced growth in aortic smooth muscle cells. J Cell Physiol 2002;193:103–109.
Cao L, Gardner DG. Natriuretic peptides inhibit DNA synthesis in cardiac fibroblasts. Hypertension 1995;25:227–234.
Knowles J, Esposito G, Mao L, Hagman J, Fox J, Smithies O, Rockman H, Maeda N. Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice. J Clin Invest 2001;107:975–984.
Oliver P, Fox J, Kim R, Rockman H, Kim HS, Reddick R, Pandey K, Milgram S, Smithies O, Maeda N. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A. Proc Natl Acad Sci USA 1997;94:14730–14735.
Ellmers LJ, Knowles JW, Kim H-S, Smithies O, Maeda N, Cameron VA. Ventricular expression of natriuretic peptides in Npr1−/− mice with cardiac hypertrophy and fibrosis. Am J Physiol Heart Circ Physiol 2002;283:H707–H714.
Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M, Itoh H, Saito Y, Tanaka I, Otani H, Katsuki M. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci USA 2000;97:4239–4244.
Ito T, Yoshimura M, Nakamura S, Nakayama M, Shimasaki Y, Harada E, Mizuno Y, Yamamuro M, Harada M, Saito Y, Nakao K, Kurihara H, Yasue H. Circulation 2003;107:807–810.
Takizawa T, Gu M, Chobanian A, Brecher P. Effect of nitric oxide on DNA replication induced by angiotensin II in rat cardiac fibroblasts. Hypertension 1997;30:1035–1040.
Numaguchi K, Egashira K, Takemoto M, Kadokami T, Shimokawa H, Sueishi K, Takeshita A. Chronic inhibition of nitric oxide synthesis causes coronary microvascular remodeling in rats. Hypertension 1995;26:957–962.
Takemoto M, Egashira K, Usui M, T Numaguchi K, Tomita H, Tsutsui H, Shimowaka H Sueishi K, Takeshita A. Important role of angiotensin-converting enzyme activity in the pathogenesis of coronary vascular and myocardial structural changes induced by long-term blockade of nitric oxide synthesis in rats. J Clin Invest 1997;99:278–287.
Tomita H, Egashira K, Ohara Y, Takemoto M, Koyanagi, M, Katoh, M, Yamamoto H, Tamaki K, Shimokawa H, Takeshita A. Early induction of growth factor-ß via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 1998;32:273–279.
Liu Y-H, Xu, J, Yang X-P, Yang F, Shesely E, Carretero OA. Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure. Hypertension 2002;39:375–381.
Ozaki M, Kawashima S, Yamashita T, Hirase T, Ohashi Y, Inoue N, Hirata K-I, Yokoyama M. Overexpression of endothelial nitric oxide synthase attenuates cardiac hypertrophy induced by chronic isoproterenol infusion. Circ J 2002;66:851–856.
Zaragoza C, Balbin M, Lopez-Otin C, Lamas S. Nitric oxide regulates matrix metalloprotease-13 expression and activity in endothelium. Kidney Int 2002;61:804–808.
Zaragoza C, Soria E, Lopez E, Browning D, Balbin M, Lopez-Otin C, Lamas S. Activation of the mitogen activated protein kinase extracellular signal-regulated kinase 1 and 2 by the nitric oxide-cGMP-cGMP-dependent protein kinase axis regulates the expression of matrix metalloproteinase 13 in vascular endothelial cells. Mol Pharmacol 2002;62:927–935.
Yoshida M, Sagawa N, Itoh H, Yura S, Korita D, Kakui K, Hirota N, Sato T, Ito A, Fujii S. Nitric oxide increases matrix metalloproteinase-1 production in human uterine cervical fibroblast cells. Mol Hum Reprod 2001;7:979–985.
Orucevic A, Bechberger J, Green AM, Shapiro RA, Billiar TR, Lala PK. Nitric-oxide production by murine mammary adenocarcinoma cells promotes tumor-cell invasiveness. Int J Cancer 1999;81:889–896.
Franchi A, Santucci M, Masini E, Sardi I, Paglierani M, Gallo O. Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 9 in carcinoma of the head and neck. Cancer 2002;95:1902–1910.
Death AK, Nakhla S, McGrath KC, Martell S, Yue DK, Jessup W, Celermajer DS. Nitroglycerin upregulates matrix metalloproteinase expression by human macrophages. J AmColl Cardiol 2002;39:1943–1950.
Eberhardt W, Beeg T, Beck KF, Walpen S, Gauer S, Bohles H, Pfeilschifter J. Nitric oxide modulates expression of matrix metalloproteinase-9 in rat mesangial cells. Kidney Int 2000;57:59–69.
Gurjar MV, Sharma RV, Bhalla RC. eNOS gene transfer inhibits smooth muscle cell migration and MMP-2 and MMP-9 activity. Arterioscler Thromb Vasc Biol 1999;19:2871–2877.
Nagatomo Y, Carabello BA, Coker ML, McDermott PJ, Nemoto S, Hamawaki M, Spinale FG. Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control. Am J Physiol Heart Circ Physiol 2000;278:H151–H161.
Li YY, Feng Y, McTiernan CF, Pei W, Moravec CS, Wang P, Rosenblum W, Kormos RL, Feldman AM. Downregulation of matrix metalloproteinases and reduction in collagen damage in the failing human heart after support with left ventricular assist devices. Circulation 2001;104:1147–1152.
Bergman MR, Cheng S, Honbo N, Piacentini L, Karliner JS, Lovett DH. A functional activating protein 1 (AP-1) site regulates matrix metalloproteinase 2 (MMP-2) transcription by cardiac cells through interactions with JunB-Fra1 and JunB-FosB heterodimers. Biochem J 2003;369:485–496.
Peterson JT, Li H, Dillon L, Bryant JW. Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat. Cardiovasc Res 2000;46:307–315.
Podesser BK, Siwik DA, Eberli FR, Sam F, Ngoy S, Lambert J, Ngo K, Apstein CS, Colucci WS. ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat. Am J Physiol Heart Circ Physiol 2001;280:H984–H991.
Fraccarollo D, Galuppo P, Bauersachs J, Ertl G. Collagen accumulation after myocardial infarction: Effects of ETA receptor blockade and implications for early remodeling. Cardiovasc Res 2002;54:559–567.
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Tsuruda, T., Costello-Boerrigter, L.C. & Burnett, J.C. Matrix Metalloproteinases: Pathways of Induction by Bioactive Molecules. Heart Fail Rev 9, 53–61 (2004). https://doi.org/10.1023/B:HREV.0000011394.34355.bb
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DOI: https://doi.org/10.1023/B:HREV.0000011394.34355.bb