(Verbatim from the application): A central component in the development and progression of congestive heart failure (CHF) is left ventricular (LV) remodeling. An important constituent of the LV myocardium is the fibrilIar collagen matrix, which has been proposed to contribute to the maintenance of LV geometry and the structural alignment of adjoining myocytes. An endogenous family of enzymes responsible for extracellular collagen degradation and remodeling is the matrix metalloproteinases, or MMPs. Recent studies have identified increased myocardial expression and activation of certain species of MMPs within the development and progression of CHF. Thus, increased LV myocardial MMP expression and activation are likely contributory mechanisms for the progressive LV remodeling in CHF. The overall goal of this continuing project is to define the mechanisms that contribute to myocardial MMP activation and to develop strategies to inhibit this process with the development and progression of CIIF. Studies will be performed which will address three specific hypotheses regarding the determinants of MMP activity within the extracellular space: transcription, activation and inhibition/deactivation: (1) A local MMP induction-activation system at the level of the LV myocyte contributes to myocardial MMP activation in CHF; (2) Controlling certain species of MMPs, such as MMP-3 expression and activity, will reduce overall myocardial MMP activity and thereby influence the LV remodeling process with developing CHF; (3) alterations in the endogenous inhibitors of the metalloproteinases (TIMPs) within the LV myocardium contributes to the LV myocardial remodeling process and the progression to CHF. In order to move the findings from these basic studies to clinical applications, this research project will develop high throughoutput and sensitive screening systems for detecting myocardial MMP expression and activity in patients with CHF and define the temporal relation between MMP activation and the LV remodeling process. These diagnostic tools will form the basis by which to identify the therapeutic window for strategies targeted at myocardial MMP inhibition. Through a focused series of integrative studies, contributory cellular and molecular mechanisms that contribute to the LV remodeling process with CHF will be identified and therapeutic strategies developed which will slow the progression of this fatal disease.
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