MOLECULAR AND CELLULAR BIOLOGY OF CARDIAC INTERSTITIUM

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The myocardium consists of three compartments: muscle, vasculature; and interstitium. Resorption and remodeling as part of collagen turnover, involves an initial degradation of fibrillar collagen by tissue collagenases. Accumulation of collagen in normal or pathological states can result from either enhanced collagen synthesis or inhibited collagenolytic mechanism. During natural growth and in various disease states associated with hypertrophic growth of the myocardium an impressive structural remodeling of the cardiac interstitium is evident. To date little is known about the contribution of collagenase to the remodeling of the cardiac interstitium in the normal and hypertrophied myocardium. The overall objective of this project is to study collagenase gene expression in the myocardium and to link collagenase gene regulation to the remodeling of the collagen matrix in the heart. Toward this end we will examine: collagenase gene expression in the normal myocardium and collagenase gene regulation at transcriptional level by nuclear run-on assay; post-transcriptional level by measurement of steady state levels of mRNA; and post-translational level by measurement of enzyme activity in left ventricular pressure overload hypertrophy. We will also examine the regulatory effects of transforming growth factor-beta on collagenase gene expression in cardiac cell culture.