Matrix Metalloproteinases: Pathways of Induction by Bioactive Molecules

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.

Matrix metalloproteinase-2 stimulates collagen-I expression through phosphorylation of focal adhesion kinase in rat cardiac fibroblasts

“…As catecholamines evoke endogenous MMP-2 expression/activation and collagen-I synthesis in fibroblasts (2,19,28,38), we stimulated the cardiac fibroblasts with 10 Ϫ6 M NE to induce the endogenous expression of MMP-2. As shown in Fig.…”

Matrix metalloproteinase‐2 expression and promoter/enhancer activity in skeletal muscle atrophy

“…MMPs are capable of degrading all components of the extracellular matrix, as well as proteolytically activating other proteases and receptors. [6][7][8][9][10][11] MMP-2 substrates include many important components of the extracellular matrix of connective tissues, such as type I, IV, X, and XI collagens, elastin, entactin, fibrillin, fibronectin, and laminin-5. 12 Elevated MMP-2 activity is observed in various physiological and pathological events related to basement membrane metabolism, such as tissue repair, angiogenesis, tumor invasion and metastasis, and arterial enlargement.…”

Dynamic interactions between cells and their extracellular matrix mediate embryonic development

“…Much of the dynamic remodeling of the ECM is dependent upon matrix metalloproteases (MMPs) and members of the a disintegrin and metalloprotease (ADAM) and a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) families. Pro-MMPs lie dormant within the ECM and are activated by various signals (Murphy et al, 1999;Davidson et al, 2002;Tsuruda et al, 2004;Nagase et al, 2006;Amalinei et al, 2007;Ra and 2008). Misregulation of MMP activity contributes to multiple diseases (metastatic carcinoma, cardiovascular disease, rheumatoid arthritis, osteoarthritis, oral diseases) and is also implicated in preterm labor (Davidson et al, 2002;Abraham et al, 2005;Hofmann et al, 2005;Vadillo-Ortega and Estrada-Gutierrez, 2005;Lemaitre and D'Armiento, 2006;Liu et al, 2006;Mon et al, 2006;Cockle et al, 2007).…”