The heart's size, shape, and function are regulated by the dynamic interaction between components of the extracellular matrix (ECM), specific cell surface receptors (integrins), the cytoskeleton, and intrinsic genetic regulation of cellular function. We know from developmental studies that integrins are important structural elements which mediate the attachment of cardiac myocytes and fibroblasts to the ECM. In addition to their structural role, integrins mediate both chemical (i.e., cytokines and growth factors) and mechanical signal transduction which is essential in modulating cellular phenotype, intracellular signaling cascades, gene transcription, and ECM remodeling in cardiovascular development. However, virtually no studies have been performed to investigate the role of integrins in the normal or diseased adult heart. Abnormalities in the interaction between myocardial integrins and the ECM represent a common pathway that could lead to the adverse structural and functional alterations which occur secondary to chronic pressure or volume overload. The proposed studies are designed to test the hypothesis that alterations in the dynamic interaction between myocardial integrins and the ECM are responsible for the adverse ventricular remodeling resulting in the transition to heart failure. The overall objective of this proposal is to investigate the relationship between myocardial integrins, cardiomyocyte hypertrophy, and ventricular remodeling which lead to the development of heart failure. Accordingly, this proposal will use a fistula model of chronic ventricular volume overload and an aortic coarctation model of pressure overload to examine cardiac function in the intact animal and at the cellular and molecular levels.
The specific aims of the proposal are 1) describe the in vivo temporal and spatial expression of specific integrins, MMPs, collagens during compensatory ventricular remodeling progressing to heart failure; 2) characterize temporal patterns of in vitro cellular function and synthesis of integrins, MMPs, and collagens in isolated cardiomyocytes and fibroblasts; and 3) determine whether perturbations in integrin expression in vitro can restore normal cellular function. These studies will utilize a variety of physiologic, morphologic, biochemical and molecular techniques to analyze the dynamic interaction between the cardiac ECM, integrins, and gene expression at critical pathophysiological stages in progressive ventricular remodeling.
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