MYOCARDIAL COLLAGEN GENE EXPRESSION--HORMONAL REGULATION

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DESCRIPTION: (Adapted from the Investigator's Abstract) It is now well recognized that the remodeling of the fibrillar collagen matrix that occurs in ventricular hypertrophy may adversely alter myocardial stiffness and lead to heart failure. The investigators have established that in ventricular hypertrophy induced by hemodynamic and hormonal stimuli the remodeling of collagen matrix is linked to alterations in collagen gene expression. They discovered that in contrast to animal models of ventricular hypertrophy induced by abdominal aortic banding and infusion of hypertensive doses of norepinephrine, thyroid hormone induced ventricular hypertrophy is not associated with cardiac fibrosis and is characterized by decrease in collagen type I gene expression. In vitro studies have demonstrated that thyroid hormone induced inhibition of the activity of collagen type I promoter occurs in cardiac fibroblast and changes in the stability of collagen type I mRNA take place. The hypothesis is that the thyroid hormone induced inhibition of collagen type I gene expression in cardiac fibroblast is mediated by the interaction of thyroid hormone induced nuclear proteins with thyroid hormone response elements on collagen type I promoter and that the activator proteins (AP-1) participates in the negative regulation of collagen gene expression by thyroid hormones. The objective, therefore, is to identify the cis-acting elements and the trans-acting factors involved in thyroid hormone induced inhibition of collagen type I gene expression in cardiac fibroblast. The results are expected to help in elucidation of the thyroid hormone sensitive pathways involved in the remodeling of the heart collagen matrix in pathological conditions and during development and growth.