Matrix Metalloproteinases

Abstract

Abstract-Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes responsible for myocardial extracellular protein degradation. Several MMP species identified within the human myocardium may be dysregulated in congestive heart failure (CHF). For example, MMPs that are expressed at very low levels in normal myocardium, such as collagenase-3 (MMP-13) and the membrane-type-1 MMPs, are substantially upregulated in CHF. However, MMP species are not uniformly increased in patients with end-stage CHF, suggesting that a specific portfolio of MMPs are expressed in the failing myocardium. With the use of animal models of CHF, a mechanistic relationship has been demonstrated with respect to myocardial MMP expression and the left ventricular (LV) remodeling process. The tissue inhibitors of the MMPs (TIMPs) are locally synthesized proteins that bind to active MMPs and thereby regulate net proteolytic activity. However, there does not appear to be a concomitant increase in myocardial TIMPs during the LV remodeling process and progression to CHF. This disparity between MMP and TIMP levels favors a persistent MMP activation state within the myocardium and likely contributes to the LV remodeling process in the setting of developing CHF. The elucidation of upstream signaling mechanisms that contribute to the selective induction of MMP species within the myocardium as well as strategies to normalize the balance between MMPs and TIMPs may yield some therapeutic strategies by which to control myocardial extracellular remodeling and thereby slow the progression of the CHF process. (Circ Res. 2002;90:520-530.)Key Words: myocardial remodeling Ⅲ heart failure Ⅲ matrix metalloproteinases Ⅲ matrix metalloproteinase inhibitors

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…Similarly, fetal gene expression and interstitial fibrosis in the LV myocardium were increased in all phenotypes and most strikingly in the MOD phenotype. Moreover, MMP‐2 and MMP‐9 expression was increased, but more importantly, TIMP‐1 expression was robustly decreased in the MOD phenotype, suggesting robust increases in MMP‐2 and MMP‐9 activities and extracellular matrix remodeling in this phenotype and as previously shown 20, 21, 22. These data further highlight the important role of TIMP‐1 as a nodal modulator of MMPs activity, extracellular matrix and myocardial remodeling, at least in this model of HF and similar to what has been shown in human HF 19…”

“…Given that the extracellular matrix was severely remodeled in the MOD phenotype, more so than the CR and MILD phenotypes, we sought to check for the expression of the MMPs, particularly the gelatinases MMP‐2 and MMP‐9 and the tissue inhibitors of MMPs, TIMP‐1, and TIMP‐2, which have been shown to play a role in myocardial diastolic stiffening and remodeling 19, 20, 21, 22, 23. Immunoblotting showed increase in MMP‐2 expression in the CR and MILD phenotypes compared with sham and was further increased in the MOD phenotype compared with sham, CR, and MILD.…”

Distinct regulation of B-type natriuretic peptide transcription by p38 MAPK isoforms

“…We show that WT p38α+MKK3b(E) overexpression significantly increased CTGF mRNA levels both in vitro and in vivo. MMP-9, another important protein that critically contributes to the re-organization of extracellular matrix (Spinale, 2002), was activated in cultured cells by overexpression of WT p38α+MKK3b(E), but not by WT p38+MKK6b(E), whereas in in vivo studies, the overexpression of p38 together with MKK6b(E) was sufficient to induce MMP-9 gene expression. However, there were no differences in COL1A1 mRNA levels in WT p38α+MKK3b(E)-transduced cells.…”

Serum markers of angiogenesis and myocardial ultrasonic tissue characterization in patients with dilated cardiomyopathy

“…In the present study, we demonstrated both increased calibrated IB and reduced CV-IB in our patients as well as a close association between calibrated IB and LV size in DCM. Myocardial extracellular matrix is composed of a complex network of structural protein, mainly collagen types I and III, and degradation of the extracellular matrix during the remodeling process reportedly occurs within the LV myocardium in DCM [15]. Matrix metalloproteinases (MMPs) have been shown to exist in the myocardium, and to be involved in degrading collagen.…”

“…Matrix metalloproteinases (MMPs) have been shown to exist in the myocardium, and to be involved in degrading collagen. Thus, a progressive activation of MMPs results in degradation of the fibrillar collagen matrix, and can lead to increased LV wall thinning and LV enlargement [15]. Recent clinical reports have demonstrated alterations in both myocardial and circulating activities of MMPs in patients with DCM [16][17][18].…”