High Blood Pressure & Cardiovascular Prevention

, Volume 17, Issue 4, pp 201–208

Matrix Metalloproteinases and their Inhibitors in Hypertensive Cardiac Remodelling

  • Chiara Marchesi
  • Andrea M. Maresca
  • Anna M. Grandi
Review Article


Arterial hypertension is a main cause of cardiac remodelling, which is characterized by left ventricular hypertrophy and diastolic dysfunction. Cardiac remodelling is associated with modifications of the extracellular matrix. The molecular structure of the extracellular matrix is controlled by proteolytic enzymes called matrix metalloproteinases (MMPs), which degrade collage, elastin, fibronectin and proteoglycans. The activity of MMPs is modulated by their natural inhibitors, the tissue inhibitors of MMPs (TIMPs), which bind the MMPs, preventing their proteolytic action. In hypertension, MMPs and TIMPs may contribute to cardiac remodelling by altering the composition of the extracellular matrix. Clinical studies in hypertensive patients have shown modulation of plasmatic concentration of MMPs and TIMPs. Also, plasmatic concentration of MMPs and TIMPs seem to be predictive of left ventricular hypertrophy, diastolic dysfunction and heart failure in hypertensive patients. However, the different technical approaches as well as the complexity of the MMP/TIMP system render it difficult to get a consensus on the pattern of their plasmatic changes in hypertension. These limitations might be overcome by large and prospective additional studies, providing a definite answer about the role of plasmatic MMPs and TIMPs as biomarkers of cardiac remodelling in hypertensive patients.


biomarkers diastolic dysfunction extracellular left ventricular hypertrophy 


  1. 1.
    Abhayaratna WP, Marwick TH, Smith WT, et al. Characteristics of left ventricular diastolic dysfunction in the community: an echocardiographic survey. Heart 2006; 92(9): 1259–64PubMedCrossRefGoogle Scholar
  2. 2.
    Levy D, Larson MG, Vasan RS, et al. The progression from hypertension to congestive heart failure. JAMA 1996; 275(20): 1557–62PubMedCrossRefGoogle Scholar
  3. 3.
    Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest 2007; 117(3): 568–75PubMedCrossRefGoogle Scholar
  4. 4.
    Brilla CG, Maisch B, Weber KT. Myocardial collagen matrix remodelling in arterial hypertension. Eur Heart J 1992; 13Suppl. D: 24–32PubMedGoogle Scholar
  5. 5.
    Tayebjee MH, MacFadyen RJ, Lip GY. Extracellular matrix biology: a new frontier in linking the pathology and therapy of hypertension? J Hypertens 2003; 21(12): 2211–8PubMedCrossRefGoogle Scholar
  6. 6.
    Ahmed SH, Clark LL, Pennington WR, et al. Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 2006; 113(17): 2089–96PubMedCrossRefGoogle Scholar
  7. 7.
    Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 2008; 75(2): 346–59PubMedCrossRefGoogle Scholar
  8. 8.
    Ammarguellat FZ, Gannon PO, Amiri F, et al. Fibrosis, matrix metalloproteinases, and inflammation in the heart of DOCA-salt hypertensive rats: role of ET(A) receptors. Hypertension 2002; 39(2 Pt 2): 679–84PubMedCrossRefGoogle Scholar
  9. 9.
    Heymans S, Schroen B, Vermeersch P, et al. Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation 2005; 112(8): 1136–44PubMedCrossRefGoogle Scholar
  10. 10.
    Castro MM, Rizzi E, Prado CM, et al. Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. Matrix Biol 2010; 29(3): 194–201PubMedCrossRefGoogle Scholar
  11. 11.
    Panek AN, Bader M. Matrix reloaded: the matrix metalloproteinase paradox. Hypertension 2006; 47(4): 640–1PubMedCrossRefGoogle Scholar
  12. 12.
    Gonzalez A, Lopez B, Ravassa S, et al. Biochemical markers of myocardial remodelling in hypertensive heart disease. Cardiovasc Res 2009; 81(3): 509–18PubMedCrossRefGoogle Scholar
  13. 13.
    Ho CY, Lopez B, Coelho-Filho OR, et al. Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med 2010; 363(6): 552–63PubMedCrossRefGoogle Scholar
  14. 14.
    Aurigemma GP, Gaasch WH. Clinical practice: diastolic heart failure. N Engl J Med 2004; 351(11): 1097–105PubMedCrossRefGoogle Scholar
  15. 15.
    Lopez B, Gonzalez A, Diez J. Circulating biomarkers of collagen metabolism in cardiac diseases. Circulation 2010; 121(14): 1645–54PubMedCrossRefGoogle Scholar
  16. 16.
    Lijnen PJ, Petrov VV. Role of intracardiac renin-angiotensin-aldosterone system in extracellular matrix remodeling. Methods Find Exp Clin Pharmacol 2003; 25(7): 541–64PubMedCrossRefGoogle Scholar
  17. 17.
    Di ZA, Cat AN, Soukaseum C, et al. Cross-talk between mineralocorticoid and angiotensin II signaling for cardiac remodeling. Hypertension 2008; 52(6): 1060–7CrossRefGoogle Scholar
  18. 18.
    Yamada T, Nagata K, Cheng XW, et al. Long-term administration of nifedipine attenuates cardiac remodeling and diastolic heart failure in hypertensive rats. Eur J Pharmacol 2009; 615(1-3): 163–70PubMedCrossRefGoogle Scholar
  19. 19.
    Eghbali M, Weber KT. Collagen and the myocardium: fibrillar structure, biosynthesis and degradation in relation to hypertrophy and its regression. Mol Cell Biochem 1990; 96(1): 1–14PubMedCrossRefGoogle Scholar
  20. 20.
    Intengan HD, Schiffrin EL. Vascular remodeling in hypertension: roles of apoptosis, inflammation, and fibrosis. Hypertension 2001; 38(3 Pt 2): 581–7PubMedCrossRefGoogle Scholar
  21. 21.
    Swynghedauw B. Phenotypic plasticity of adult myocardium: molecular mechanisms. J Exp Biol 2006; 209(Pt 12): 2320–7PubMedCrossRefGoogle Scholar
  22. 22.
    Weber KT. Cardioreparation in hypertensive heart disease. Hypertension 2001; 38(3 Pt 2): 588–91PubMedCrossRefGoogle Scholar
  23. 23.
    Zile MR, Brutsaert DL. New concepts in diastolic dysfunction and diastolic heart failure, part II: causal mechanisms and treatment. Circulation 2002; 105(12): 1503–8PubMedCrossRefGoogle Scholar
  24. 24.
    Yamazaki T, Shiojima I, Komuro I, et al. Interaction of cardiac myocytes and non-myocytes in mechanical stress-induced hypertrophy. Herz 1995; 20(2): 109–17PubMedGoogle Scholar
  25. 25.
    Levick SP, Brower GL. Regulation of matrix metalloproteinases is at the heart of myocardial remodeling. Am J Physiol Heart Circ Physiol 2008; 295(4): H1375–6PubMedCrossRefGoogle Scholar
  26. 26.
    Clark IM, Swingler TE, Sampieri CL, et al. The regulation of matrix metalloproteinases and their inhibitors. Int J Biochem Cell Biol 2008; 40(6-7): 1362–78PubMedCrossRefGoogle Scholar
  27. 27.
    Siwik DA, Kuster GM, Brahmbhatt JV, et al. EMMPRIN mediates beta-adrenergic receptor-stimulated matrix metalloproteinase activity in cardiac myocytes. J Mol Cell Cardiol 2008; 44(1): 210–7PubMedCrossRefGoogle Scholar
  28. 28.
    Nie R, Xie S, Du B, et al. Extracellular matrix metalloproteinase inducer (EMMPRIN) is increased in human left ventricle after acute myocardial infarction. Arch Med Res 2009; 40(7): 605–11PubMedCrossRefGoogle Scholar
  29. 29.
    Dorman G, Kocsis-Szommer K, Spadoni C, et al. MMP inhibitors in cardiac diseases: an update. Recent Pat Cardiovasc Drug Discov 2007; 2(3): 186–94PubMedCrossRefGoogle Scholar
  30. 30.
    Diez J, Gonzalez A, Lopez B, et al. Mechanisms of disease: pathologic structural remodeling is more than adaptive hypertrophy in hypertensive heart disease. Nat Clin Pract Cardiovasc Med 2005; 2(4): 209–16PubMedCrossRefGoogle Scholar
  31. 31.
    Wagner DR, Delagardelle C, Ernens I, et al. Matrix metalloproteinase-9 is a marker of heart failure after acute myocardial infarction. J Card Fail 2006; 12(1): 66–72PubMedCrossRefGoogle Scholar
  32. 32.
    López B, Gonzalez A, Querejeta R, et al. Alterations in the pattern of collagen deposition may contribute to the deterioration of systolic function in hypertensive patients with heart failure. J Am Coll Cardiol 2006; 48(1): 89–96PubMedCrossRefGoogle Scholar
  33. 33.
    Kelly D, Khan SQ, Thompson M, et al. Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction. Eur Heart J 2008; 29(17): 2116–24PubMedCrossRefGoogle Scholar
  34. 34.
    Sakata Y, Yamamoto K, Mano T, et al. Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats: its inhibition as a primary effect of angiotensin-converting enzyme inhibitor. Circulation 2004; 109(17): 2143–9PubMedCrossRefGoogle Scholar
  35. 35.
    Brassard P, Amiri F, Schiffrin EL. Combined angiotensin II type 1 and type 2 receptor blockade on vascular remodeling and matrix metalloproteinases in resistance arteries. Hypertension 2005; 46(3): 598–606PubMedCrossRefGoogle Scholar
  36. 36.
    Deschamps AM, Apple KA, Leonardi AH, et al. Myocardial interstitial matrix metalloproteinase activity is altered by mechanical changes in LV load: interaction with the angiotensin type 1 receptor. Circ Res 2005; 96(10): 1110–8PubMedCrossRefGoogle Scholar
  37. 37.
    Funck RC, Wilke A, Rupp H, et al. Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease. Adv Exp Med Biol 1997; 432: 35–44PubMedCrossRefGoogle Scholar
  38. 38.
    Wang Y, Ait-Oufella H, Herbin O, et al. TGF-beta activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Invest 2010; 120(2): 422–32PubMedCrossRefGoogle Scholar
  39. 39.
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, et al. High serum matrix metalloproteinase-9 level predict increased risk of in-hospital cardiac events in patients with type 2 diabetes and ST segment elevation myocardial infarction. Atherosclerosis 2008; 196(1): 365–71PubMedCrossRefGoogle Scholar
  40. 40.
    Cavusoglu E, Ruwende C, Chopra V, et al. Tissue inhibitor of metalloproteinase-1 (TIMP-1) is an independent predictor of all-cause mortality, cardiac mortality, and myocardial infarction. Am Heart J 2006; 151(5): 1101–8PubMedCrossRefGoogle Scholar
  41. 41.
    Jefferis BJ, Whincup P, Welsh P, et al. Prospective study of matrix metalloproteinase-9 and risk of myocardial infarction and stroke in older men and women. Atherosclerosis 2010; 208(2): 557–63PubMedCrossRefGoogle Scholar
  42. 42.
    Wu TC, Leu HB, Lin WT, et al. Plasma matrix metalloproteinase-3 level is an independent prognostic factor in stable coronary artery disease. Eur J Clin Invest 2005; 35(9): 537–45PubMedCrossRefGoogle Scholar
  43. 43.
    Tuomainen AM, Nyyssonen K, Laukkanen JA, et al. Serum matrix metalloproteinase-8 concentrations are associated with cardiovascular outcome in men. Arterioscler Thromb Vasc Biol 2007; 27(12): 2722–8PubMedCrossRefGoogle Scholar
  44. 44.
    Arenillas JF, Alvarez-Sabin J, Molina CA, et al. Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis. Stroke 2008; 39(5): 1456–63PubMedCrossRefGoogle Scholar
  45. 45.
    Heo JH, Kim SH, Lee KY, et al. Increase in plasma matrix metalloproteinase-9 in acute stroke patients with thrombolysis failure. Stroke 2003; 34(6): e48–50PubMedCrossRefGoogle Scholar
  46. 46.
    Loftus IM, Naylor AR, Goodall S, et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques: a potential role in acute plaque disruption. Stroke 2000; 31(1): 40–7PubMedCrossRefGoogle Scholar
  47. 47.
    Velagaleti RS, Gona P, Sundstrom J, et al. Relations of biomarkers of extracellular matrix remodeling to incident cardiovascular events and mortality. Arterioscler Thromb Vasc Biol 2010; 30(11): 2283–8PubMedCrossRefGoogle Scholar
  48. 48.
    Nagatomo Y, Carabello BA, Coker ML, et al. Differential effects of pressure or volume overload on myocardial MMP levels and inhibitory control. Am J Physiol Heart Circ Physiol 2000; 278(1): H151–61PubMedGoogle Scholar
  49. 49.
    Matsusaka H, Ide T, Matsushima S, et al. Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension 2006; 47(4): 711–7PubMedCrossRefGoogle Scholar
  50. 50.
    Heymans S, Lupu F, Terclavers S, et al. Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. Am J Pathol 2005; 166(1): 15–25PubMedCrossRefGoogle Scholar
  51. 51.
    Kassiri Z, Oudit GY, Sanchez O, et al. Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. Circ Res 2005; 97(4): 380–90PubMedCrossRefGoogle Scholar
  52. 52.
    Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 2009; 78(6): 539–52PubMedCrossRefGoogle Scholar
  53. 53.
    Wright JL, Tai H, Wang R, et al. Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-alpha signaling. Am J Physiol Lung Cell Mol Physiol 2007; 292(1): L125–33PubMedCrossRefGoogle Scholar
  54. 54.
    Starckx S, Van den Steen PE, Wuyts A, et al. Neutrophil gelatinase B and chemokines in leukocytosis and stem cell mobilization. Leuk Lymphoma 2002; 43(2): 233–41PubMedCrossRefGoogle Scholar
  55. 55.
    Siwik DA, Colucci WS. Regulation of matrix metalloproteinases by cytokines and reactive oxygen/nitrogen species in the myocardium. Heart Fail Rev 2004; 9(1): 43–51PubMedCrossRefGoogle Scholar
  56. 56.
    Matsusaka H, Ikeuchi M, Matsushima S, et al. Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy. Am J Physiol Heart Circ Physiol 2005; 289(5): H1858–64PubMedCrossRefGoogle Scholar
  57. 57.
    Tayebjee MH, Nadar S, Blann AD, et al. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Am J Hypertens 2004; 17(9): 764–9PubMedGoogle Scholar
  58. 58.
    Yasmin, McEniery CM, Wallace S, et al. Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness. Arterioscler Thromb Vasc Biol 2005; 25(2): 372PubMedCrossRefGoogle Scholar
  59. 59.
    Franz M, Berndt A, Altendorf-Hofmann A, et al. Serum levels of large tenascin-C variants, matrix metalloproteinase-9, and tissue inhibitors of matrix metalloproteinases in concentric versus eccentric left ventricular hypertrophy. Eur J Heart Fail 2009; 11(11): 1057–62PubMedCrossRefGoogle Scholar
  60. 60.
    Onal IK, Altun B, Onal ED, et al. Serum levels of MMP-9 and TIMP-1 in primary hypertension and effect of antihypertensive treatment. Eur J Intern Med 2009; 20(4): 369–72PubMedCrossRefGoogle Scholar
  61. 61.
    Saglam M, Karakaya O, Esen AM, et al. Contribution of plasma matrix metalloproteinases to development of left ventricular hypertrophy and diastolic dysfunction in hypertensive subjects. Tohoku J Exp Med 2006; 208(2): 117–22PubMedCrossRefGoogle Scholar
  62. 62.
    Friese RS, Rao F, Khandrika S, et al. Matrix metalloproteinases: discrete elevations in essential hypertension and hypertensive end-stage renal disease. Clin Exp Hypertens 2009; 31(7): 521–33PubMedCrossRefGoogle Scholar
  63. 63.
    Tayebjee MH, Lim HS, Nadar S, et al. Tissue inhibitor of metalloproteinse-1 is a marker of diastolic dysfunction using tissue doppler in patients with type 2 diabetes and hypertension. Eur J Clin Invest 2005; 35(1): 8–12PubMedCrossRefGoogle Scholar
  64. 64.
    Tayebjee MH, Karalis I, Nadar SK, et al. Circulating matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases-1 and -2 levels in gestational hypertension. Am J Hypertens 2005; 18(3): 325–9PubMedCrossRefGoogle Scholar
  65. 65.
    Laviades C, Varo N, Fernandez J, et al. Abnormalities of the extracellular degradation of collagen type I in essential hypertension. Circulation 1998; 98(6): 535–40PubMedCrossRefGoogle Scholar
  66. 66.
    Li-Saw-Hee FL, Edmunds E, Blann AD, et al. 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(1): 43–7PubMedCrossRefGoogle Scholar
  67. 67.
    Tayebjee MH, Nadar SK, MacFadyen RJ, et al. Tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9 levels in patients with hypertension: relationship to tissue Doppler indices of diastolic relaxation. Am J Hypertens 2004; 17(9): 770–4PubMedGoogle Scholar
  68. 68.
    Tan J, Hua Q, Xing X, et al. Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension. Hypertens Res 2007; 30(10): 959–63PubMedCrossRefGoogle Scholar
  69. 69.
    Stakos DA, Tziakas DN, Chalikias GK, et al. Associations between collagen synthesis and degradation and aortic function in arterial hypertension. Am J Hypertens 2010; 23(5): 488–94PubMedCrossRefGoogle Scholar
  70. 70.
    McNulty M, Mahmud A, Spiers P, et al. Collagen type-I degradation is related to arterial stiffness in hypertensive and normotensive subjects. J Hum Hypertens 2006; 20(11): 867–73PubMedCrossRefGoogle Scholar
  71. 71.
    Sundström J, Evans JC, Benjamin EJ, et al. Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: the Framingham Heart Study. Circulation 2004; 109(23): 2850–6PubMedCrossRefGoogle Scholar
  72. 72.
    Hirono O, Fatema K, Nitobe J, et al. Long-term effects of benidipine hydrochloride on severe left ventricular hypertrophy and collagen metabolism in patients with essential hypertension. J Cardiol 2002; 39(4): 195–204PubMedGoogle Scholar
  73. 73.
    Martos R, Baugh J, Ledwidge M, et al. Diastolic heart failure: evidence of increased myocardial collagen turnover linked to diastolic dysfunction. Circulation 2007; 115(7): 888–95PubMedCrossRefGoogle Scholar
  74. 74.
    Dhingra R, Pencina MJ, Schrader P, et al. Relations of matrix remodeling biomarkers to blood pressure progression and incidence of hypertension in the community. Circulation 2009; 119(8): 1101–7PubMedCrossRefGoogle Scholar
  75. 75.
    Sang QX, Jin Y, Newcomer RG, et al. Matrix metalloproteinase inhibitors as prospective agents for the prevention and treatment of cardiovascular and neoplastic diseases. Curr Top Med Chem 2006; 6(4): 289–316PubMedCrossRefGoogle Scholar
  76. 76.
    Corbitt CA, Lin J, Lindsey ML. Mechanisms to inhibit matrix metalloproteinase activity: where are we in the development of clinically relevant inhibitors? Recent Pat Anticancer Drug Discov 2007; 2(2): 135–42PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Chiara Marchesi
    • 1
  • Andrea M. Maresca
    • 1
    • 2
  • Anna M. Grandi
    • 1
    • 2
  1. 1.Department of Clinical MedicineUniversity of InsubriaVareseItaly
  2. 2.Ospedale di CircoloVareseItaly

Personalised recommendations