The overall objective of these studies is to determine the inter-relationships in the heart between the renin-angiotensin system, fibronectin expression and the fibrosis associated with cardiac hypertrophy. The proposal is focused primarily on understanding the factors that influence the development of cardiac fibrosis during the progression of cardiac hypertrophy induced by chronic exposure to angiotensin II. A basic premise is that angiotensin II acts directly on cardiac cell types to induce growth factor and fibronectin expression, which in turn has a functional role in the remodeling processes associated with cardiac fibrosis. An experimental model will be developed in the intact rat where angiotensin II is infused by osmotic minipump to induce cardiac hypertrophy and fibrosis, and changes in the heart will be documented using histological and biochemical techniques.
The specific aims i nclude: 1) characterization of the temporal changes in fibronectin expression and fibrosis that occur during the chronic infusion of angiotensin II using biochemical, morphometric and physiological techniques; 2) to determine if changes in fibronectin expression are secondary to hemodynamic changes or are due to direct effects of agonists on cardiac cell types using antihypertensive drugs, or drugs that influence nitric oxide production, in conjunction with pressor or subpressor doses of angiotensin II; 3) to use in situ hybridization to measure the expression of selected growth factors thought to have an autocrine or paracrine role in mediating the angiotensin II induced changes, focusing mainly on the inter-relationships between angiotensin II, TGF-b1 and fibronectin; 4) to utilize cultured fibroblasts from neonatal rat hearts to determine the effects of added angiotensin II and TGF-b alone or in combination on fibronectin expression and cell proliferation, to test for TGF-b induction by angiotensin II as a possible autocrine loop, and to study the possible inter-relationships between angiotensin II and nitric oxide on these parameters; and to initiate studies designed to determine the intracellular signalling pathway that facilitates the effects of angiotensin II on cardiac fibroblasts.
