Collagens are the major extracellular matrix component of the heart. The ECM provides structural integrity and tensile strength to the myocardium critical to maintaining the alignment of myocytes and myofibrils, and the overall geometry of the left ventricle. Fibrillar collagen degradation and changes in structural protein content have been postulated to contribute to myocyte slippage, wall thinning, and ventricular remodeling in heart failure. Interstitial collagen is highly resistant to degradation by all proteinases other than collagenases. Using the alpha-myosin heavy chain promoter we have created a transgenic mouse which constitutively expresses interstitial collagenase in the heart. Histological and functional analysis in these animals with disrupted matrix balance reveals myocyte and myofibrillar hypertrophy, altered collagen content, and ventricular dysfunction. This research proposal will investigate the role of the ECM and the balance of the protease-antiprotease system in cardiac function and in the pathophysiology of ventricular remodeling and the development of heart failure. The cardiac-collagenase mice will be subjected to hemodynamic and mechanical conditions that may impact on the cardiac remodeling in these animals. Experiments will be performed to identify changes in intracellular signaling which occur in the heart of the cardiac-collagenase mice. Studies will also determine if MMP-1 inhibitors are capable of halting the progression of the cardiac dysfunction seen in these animals. In conjunction with the animals studies, this proposal will investigate whether changes in the extracellular matrix proteins occur during reverse remodeling seen in human LVAD samples. Finally, this proposal will investigate the role of interstitial collagenase (MMP-13) in cardiac function and development through the generation of an MMP-13 knockout mouse.
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