A Matrix Metalloproteinase Induction/Activation System Exists in the Human Left Ventricular Myocardium and Is Upregulated in Heart Failure

Abstract

Background-Matrix metalloproteinases (MMPs) contribute to matrix remodeling in disease states such as tumor metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to increase MMP expression, and membrane-type MMP or MT1-MMP has been implicated to activate MMPs. The present study examined whether and to what degree EMMPRIN and MT1-MMP were expressed in human left ventricular (LV) myocardium as well as the association with MMP activity and expression in dilated cardiomyopathy (DCM). Methods and Results-LV myocardial zymographic MMP activity increased by Ͼ2-fold with both nonischemic DCM (nϭ21) and ischemic DCM (nϭ16) compared with normal (nϭ13). LV myocardial abundance of MMP-9 was increased with both forms of DCM. MMP-2 and MMP-3 were increased with nonischemic DCM. MMP-1 levels were decreased with both forms of DCM. EMMPRIN increased by Ͼ250% and MT1-MMP increased by Ͼ1000% with both forms of DCM. Conclusions-Increased LV myocardial MMP activity and selective upregulation of MMPs with nonischemic and ischemic forms of DCM occurred. Moreover, a local MMP induction/activation system was identified in isolated normal human LV myocytes that was upregulated with DCM. The control of MMP activation and expression in the failing human LV myocardium represents a new and potentially significant therapeutic target for this disease process.

Differential Regulation of Matrix Metalloproteinase-2 and -9 Expression and Activity in Adult Rat Cardiac Fibroblasts in Response to Interleukin-1β

“…MMP-9 activity increases 1 day after MI, whereas MMP-2 activity starts to increase within 4 days after MI. Furthermore, MMP-9 abundance increases in both ischemic and non-ischemic dilated cardiomyopathy, whereas the abundance of MMP-2 increases only in non-ischemic dilated cardiomyopathy (9). These observations suggest differential regulation of MMP-2 and -9 in the heart.…”

Type IV collagen degradation in the myocardial basement membrane after unloading of the failing heart by a left ventricular assist device

“…It is known that MMP-2 is able to degrade type IV collagen and is upregulated during heart failure. 14,24,25 Because we have shown changes in cardiomyocyte size and ECM volume after unloading of the LV by LVAD support 12,15 and given the close connection between type IV collagen and the cardiomyocyte, we hypothesized that the BM surrounding the cardiomyocyte must be reshaped when the cardiomyocytes become smaller by unloading of the heart by an LVAD. If so, MMP-2 (collagenase IV) can play a major role in this process of remodeling.…”

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

“…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]. Spinale et al [18] have reported a decreased myocardial activity of the interstitial collagenase, or MMP-1, which degrades the fibrillar collagen such as collagen types I and III, as well as increased activities of gelatinases, or MMP-2 and MMP-9, in DCM.…”

“…Recent clinical reports have demonstrated alterations in both myocardial and circulating activities of MMPs in patients with DCM [16][17][18]. Spinale et al [18] have reported a decreased myocardial activity of the interstitial collagenase, or MMP-1, which degrades the fibrillar collagen such as collagen types I and III, as well as increased activities of gelatinases, or MMP-2 and MMP-9, in DCM. This reduction in MMP-1 activity may result in an increased deposition of collagen types I and III.…”