LV remodeling is a common structural event following myocardial infarction (MI), which can lead to congestive heart failure (CHF). Enzyme systems responsible for extracellular remodeling, particularly following MI, include the matrix metalloproteinases (MMPs). Pharmacological MMP inhibition can attenuate the LV remodeling process in animal models of CHF and post-MI. However, it has also been demonstrated that activation of certain MMP species may be an essential component of the initial wound healing process post-Ml. Recent results from our laboratory have demonstrated region specific induction of myocardial MMPs as well as a loss of endogenous inhibitors of MMPs (TIMPs) occurs post-Ml. Therefore the induction and activation of myocardial MMPs post-MI appears to occur in a species specific, region, and time dependent fashion. Since alterations in MMPs and TIMPs likely contribute to the remodeling process post-MI, then identifying the upstream signaling pathways which regulate MMP/TIMP induction and activation holds significant relevance. The bioactive peptide endothelin (ET) induces MMP expression in both myocytes and cardiac fibroblasts. Increased myocardial synthesis and release of ET occurs during and following MI and has been demonstrated to contribute to the progression of CHF. However, recent studies have demonstrated that initiation of ET receptor blockade early post-MI may actually accelerate infarct expansion and LV dysfunction. In contrast, ET receptor blockade initiated later in the post-MI period has been demonstrated to favorably modify the LV remodeling process, improve LV function and survival. The central hypothesis of this continuing project is that a time and region specific induction of myocardial MMPs occur post-MI which is under significant regulation of the ET system. This project will perform an integrative series of studies using a model of post-MI remodeling, murine systems of MI and ET induction, as well as in-vitro cell systems in order to identify how ET receptor activation contributes to early and late post-MI remodeling and therefore the progression to CHF. [unreadable] [unreadable]