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.

A milestone in the progression of congestive heart failure (CHF) is myocardial remodeling. Left ventricular (LV) remodeling during the progression of CHF is accompanied by changes in the structure of the myocardial extracellular matrix. Recent clinical and experimental studies have noted that increased release of tumor necrosis factor alpha (TNF-alpha) can contribute to LV myocardial remodeling. Experimental studies have noted that the induction of TNF-alpha can result in LV dilation and proceed to LV pump dysfunction. The biological effects of TNF-alpha are mediated through TNF receptors that are present on all nucleated cells in the heart. TNF receptor activation can induce a number of cellular and molecular events which contribute to LV remodeling in CHF, and include changes in myocyte size and viability and alterations in myocardial structure/composition. In vitro studies have demonstrated that TNF receptor activation can cause the induction of a proteolytic system. This proteolytic system, the matrix metalloproteinases (MMPs), is upregulated in models of LV dysfunction and possesses the capacity to degrade a wide variety of extracellular matrix components. Therefore, one pathway by which TNF-alpha can influence LV myocardial remodeling is through the induction of a specific portfolio of MMP species. Future basic and clinical studies which directly alter TNF receptor activity and measure myocardial MMP species and the relation to LV remodeling will provide new insight into this disease process and future therapeutic modalities.

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Abstract-The matrix metalloproteinases (MMPs) are an endogenous family of proteolytic enzymes implicated to contribute to LV remodeling. However, broad-spectrum MMP inhibition (MMPi), particularly inhibition of interstitial collagenase (MMP-1), may not be clinically applicable. This study examined the effects of selective MMPi (sparing MMP-1) in a model of developing congestive heart failure. Pigs were randomly assigned to 3 groups: (1) rapid pacing for 3 weeks (240 bpm, nϭ10); (2) selective MMPi (20 mg/kg per day-PO;PGE7113313) and rapid pacing (nϭ12); and (3) controls (nϭ10 Key Words: left ventricular systolic function Ⅲ myocardial stiffness Ⅲ myocardial structure Ⅲ matrix metalloproteinases Ⅲ heart failure A structural milestone in the progression of congestive heart failure (CHF) is alterations in left ventricular (LV) geometry, commonly referred to as myocardial remodeling. The myocardial extracellular matrix contributes to the maintenance of LV geometry, structural alignment of adjoining myocytes, as well as modulating transmembrane signaling pathways. A family of enzymes that contributes to extracellular collagen degradation and tissue remodeling is the matrix metalloproteinases (MMPs). 1-3 Increased expression and activity of MMPs within the LV myocardium occurs in both patients and animals with CHF. 4 -8 Orally active nonselective MMP inhibitors, termed as broad spectrum MMP inhibitors, have been used in several animal models of CHF and demonstrated to attenuate the LV remodeling process. 7-9 Therefore, modulating MMP activity represents a potential therapeutic target in the context of LV remodeling and CHF. However, long-term inhibition of all MMP species will likely interfere with normal tissue remodeling processes and can give rise to undesirable systemic effects. 10 -12 Thus, selective targeting of MMP species that contribute to pathological myocardial remodeling in developing CHF will likely hold greater therapeutic potential. Whereas a number of MMP species are expressed within the human myocardium, not all MMPs are upregulated in end-stage CHF. 6,13,14 Specifically, the abundance of interstitial collagenase-1, or MMP-1, is significantly reduced in patients with cardiomyopathic disease. 6 However, it remains unknown whether inhibition of MMP-1 is a fundamental requirement in order to alter the myocardial remodeling process during the initiation and development of CHF. Accordingly, the overall goal of this study was to institute selective MMP inhibition that would effectively spare MMP-1 inhibition in an animal model of developing CHF. Materials and Methods Selective MMP InhibitionPast studies have demonstrated that several classes of MMPs are increased in CHF including the interstitial collagenase MMP-13, stromelysins such as MMP-3, and the gelatinases such as MMP-2 and MMP-9. 4 -8,14 In order to identify an MMP inhibition dosage regimen that would provide acceptable plasma profiles with respect to inhibition of these species but effectively spare MMP-1 inhibition, pharmacokinetic studies were p...

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These unique results demonstrated that induction of a controlled myocardial injury in humans, specifically through alcohol-induced MI, caused species- and time-dependent perturbations of MMP/TIMP stoichiometry that would facilitate myocardial remodeling in the early post-MI setting.