The heart binds angiotensin II (AII) with high affinity and induces cardiac ventricular hypertrophy in a number of pathophysiologic states including suprarenal coarctation of the aorta, two kidney one-clip hypertension, and cardiocytes in culture. In addition, a large body of evidence exists in humans that AII plays an active role in the development of cardiovascular disease. Treatment with converting enzyme inhibitors to inhibit the formation of AII results in a regression in left ventricular mass with hypertensive cardiac hypertrophy, even when circulating renin levels are normal, increased survival after myocardial infarction, and in patients with severe left ventricular dysfunction. AII mediates its effects through membrane receptor binding to two subtypes of receptors the angiotensin type 1 (AT1) and AT2 both of which are present in the adult heart. The AT1 is the predominant vascular smooth muscle AII receptor with ligand binding resulting in the activation of protein kinase C and increased intracellular calcium, whereas the function of the AT2 receptor is presently not known. Given that AII has a powerful effect on heart growth in a number of pathophysiologic conditions and the presence of AII receptors in the heart, we hypothesize that AII plays a clear role in the regulation of heart growth. The objective of the proposal is to define the receptor/signaling mechanisms and cellular mediators involved in the AII regulation of cardiac hypertrophy. To do this we will make use of a novel in vitro model of cardiac hypertrophy utilizing isolated adult rat cardiocytes in culture stimulated with AII or whole animals receiving sub-hypertensive doses of AII by osmotic pump. Specifically, the hypotheses to be tested are: i) that AII/AT1 and/or AT2 receptor binding results in an upregulation of growth factors that mediate cardiac hypertrophy; 2) that AT1 or AT2 receptor mediate cardiac hypertrophy as a result of activation of the phospholipase C/protein kinase C signal-transduction pathway or via receptor translocation or both; and 3) that AII induced cardiac hypertrophy is mediated through the AT1 or AT2 receptor and results in an alteration in receptor number and gene expression. Thus, these studies will provide a detailed analysis of the AII regulation of heart growth and provide a basis for understanding the relevance of the hormone in disease states such as hypertension and heart failure.
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