Role of Matrix Metalloproteinase in the Progression of Heart Failure: A Narrative Review

Sidhi Laksono, Budhi Setianto, Reynaldo Halomoan


Heart failure (HF) is a cardiovascular disease with a complex pathological pathway and influenced by many factors. Such a complex pathological mechanism would impair cardiac function and structural stability. One that plays a role in maintaining the function and structure of the heart is the extracellular matrix (ECM), and disruption in the extracellular matrix has a role in causing cardiac dysfunction. ECM regulation is associated with matrix metalloproteinase (MMP). Overexpression of matrix metalloproteinases can lead to ECM degradation process which leads to cardiac remodelling. The role of MMP in heart failure is also related to the increased inflammatory response, which is one of the pathways for progression of heart failure. The close association of MMP with the development of heart failure makes MMP a potential biological marker. This article aims was to understand the role of MMP and its mechanisms in cardiac remodelling pathways leading to heart failure. This narrative review suggests that overexpression of MMP can lead to heart failure. Inflammation is one of the factors triggering the expression of MMP. Inflammation will increase the release of pro-inflammatory cytokines, thereby triggering MMP expression. MMP expression imbalance can damage collagen tissue through ECM degradation and damage the structure and function of the heart. MMP can also be used as a biological marker in heart failure cases. The application of MMP as a biological marker can be used to assess the degree of disease severity as well as a predictor of heart failure. In conclusion, MMP has an important role in the development process of heart failure and can be a biological marker in cases of heart failure.


extracellular matrix; heart failure; matrix metalloproteinase;mechanism

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Awad AE, Kandalam V, Chakrabarti S, Wang X, Penninger JM, et al, 2010. Tumor necrosis factor induces matrix metalloproteinases in cardiomyocytes and cardiofibroblasts differentially via superoxide production in a PI3Kγ-dependent manner. Am. J. Physiol. Physiol. 298, C679–C692.

Azevedo A, Prado AF, Antonio RC, Issa JP, Gerlach RF, 2014. Matrix metalloproteinases are involved in cardiovascular diseases. Basic Clin. Pharmacol. Toxicol. 115, 301–314.

Bayomy AF, Bauer M, Qiu Y, Liao R, 2012. Regeneration in heart disease—is ECM the key? Life Sci. 91, 823–827.

Bonnans C, Chou J, Werb Z, 2014. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. cell Biol. 15, 786–801.

DeLeon-Pennell KY, Meschiari CA, Jung M, Lindsey ML, 2017. Matrix metalloproteinases in myocardial infarction and heart failure. Prog. Mol. Biol. Transl. Sci. 147: 75–100.

Doxakis A, Polyanthi K, Androniki T, Savvas P, Eleni Z, 2019. Targeting metalloproteinases in cardiac remodeling. J Cardiovasc Med Cardiol. 6: 51–60.

Fan D, Takawale A, Lee J, Kassiri Z, 2012. Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease. Fibrogenesis Tissue Repair. 5: 15.

Fan Z, Fu M, Xu Z, Zhang B, Li Z, Li H, et al, 2017. Sustained release of a peptide-based matrix metalloproteinase-2 inhibitor to attenuate adverse cardiac remodeling and improve cardiac function following myocardial infarction. Biomacromolecules. 18: 2820–2829.

Frangogiannis NG, 2019. The extracellular matrix in ischemic and nonischemic heart failure. Circ. Res. 125: 117–146.

Frangogiannis NG, 2017. The extracellular matrix in myocardial injury, repair, and remodeling. J. Clin. Invest. 127: 1600–1612.

Frantz C, Stewart KM, Weaver VM, 2010. The extracellular matrix at a glance. J. Cell Sci. 123: 4195–4200.

Halade GV, Jin YF, Lindsey ML, 2013. Matrix metalloproteinase (MMP)-9: a proximal biomarker for cardiac remodeling and a distal biomarker for inflammation. Pharmacol. Ther. 139: 32–40.

Hutchinson KR, Stewart Jr, JA, Lucchesi PA, 2010. Extracellular matrix remodeling during the progression of volume overload-induced heart failure. J. Mol. Cell. Cardiol. 48: 564–569.

Iyer RP, de Castro Brás LE, Patterson NL, Bhowmick M, Flynn ER, Asher M, et al, 2016a. Early matrix metalloproteinase-9 inhibition post-myocardial infarction worsens cardiac dysfunction by delaying inflammation resolution. J. Mol. Cell. Cardiol. 100: 109–117.

Iyer RP, Jung M, Lindsey ML, 2016b. MMP-9 signaling in the left ventricle following myocardial infarction. Am. J. Physiol. Circ. Physiol. 311: H190–H198.

Kwak HB., 2013. Aging, exercise, and extracellular matrix in the heart. J. Exerc. Rehabil. 9: 338.

Leonard BL, Smaill BH, LeGrice IJ, 2012. Structural remodeling and mechanical function in heart failure. Microsc. Microanal. 18: 50.

Lindsey ML, Iyer RP, Jung M, DeLeon-Pennell KY, Ma Y, 2016.

Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling. J. Mol. Cell. Cardiol. 91: 134–140.

Lu P, Takai K, Weaver VM, Werb Z, 2011. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol. 3, a005058.

Ma Y, de Castro Brás LE, Toba H, Iyer RP, Hall ME, et al, 2014. Myofibroblasts and the extracellular matrix network in post-myocardial infarction cardiac remodeling. Pflügers Arch. J. Physiol. 466: 1113–1127.

Moore L, Fan D, Basu R, Kandalam V, Kassiri Z, 2012. Tissue inhibitor of metalloproteinases (TIMPs) in heart failure. Heart Fail. Rev. 17, 693–706.

Morishita T, Uzui H, Mitsuke Y, Amaya N, Kaseno K, et al, 2017. Association between matrix metalloproteinase‐9 and worsening heart failure events in patients with chronic heart failure. ESC Hear. Fail. 4: 321–330.

Spinale FG, Villarreal F, 2014. Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochem. Pharmacol. 90: 7–15.

Toba H, Cannon PL, Yabluchanskiy A, Iyer RP, D’Armiento J, et al, 2017. Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis. Am. J. Physiol. Circ. Physiol. 312: H375–H383.

Zile MR, Baicu CF, Stroud RE, Van Laer AO, Jones JA, et al, 2014. Mechanistic relationship between membrane type-1 matrix metalloproteinase and the myocardial response to pressure overload. Circ. Hear. Fail. 7: 340–350



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