Congestive heart failure secondary to dilated cardiomyopathy is a disease of epidemic proportions in the U.S. It is generally viewed as a progressive disease in which initial myocardial damage is followed by cardiac remodeling and progressive dilatation of the ventricular cavity. Thus, compensation is followed by progressive decompensation and patients present with worsening symptoms including fatigue, shortness of breath, and edema. Recent investigation has focused on the role of the pro- inflammatory cytokines TNFalpha and IL-1beta in the development of CHF and in particular in the transition from compensated to decompensated heart failure. Although TNFalpha can modulate the function of a group of potentially important cardiac proteins, recent evidence from our laboratory suggests that TNFalpha maladaptively modulate the expression of the two families of proteins that regulate the homeostatic balance within the extracellular matrix,, the matrix metalloproteinases (MMP) and the inhibitors of metalloproteinase (TIMP). Furthermore, transgenic mice harboring cardiac specific over- expression of TNFalpha develop progressive fibrosis and extracellular matrix remodeling that is associated with up-regulation of MMPs and down-regulation of TIMPs. The infiltrates (but not the fibrosis) can be ameliorated to cytokine induced extracellular matrix remodeling and fibrosis and that the development of fibrosis marks both the irreversibility and end-stage of the disease. The overall goals of this application are therefore to test this hypothesis.
In Specific Aim #1, we will test the hypothesis that the expression of cytokines are required for structural remodeling of the extracellular matrix and that remodeling is facilitated by interaction with specific cytokine receptors.
In Specific Aim #2, we will test the hypothesis that anti-cytokine therapy will prevent matrix remodeling by not ameliorate existing fibrosis. Finally, in Specific Aim #3, we will test the hypothesis that therapies designed to alter the expression of the various proteins that regulate matrix remodeling will prevent and/or hypothesis that therapies designed to alter the expression of the various proteins that regulate matrix remodeling will prevent and/or reverse maladaptive changes. These studies will utilize tow experimental models; 1) transgenic mice with cardiac-specific over-expression of TNFalpha; and 2) mice with myocardial infarcts secondary to coronary ligation.
The aims of this application will be further supported by the availability of mice harboring mutations in selected cytokine receptors as well as recombinant AAV vectors expressing MMPs and TIMPs and transgenic mice harboring mutations in selected proteinases.
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