CARDIAC ANGIOTENSIN--LOAD INDUCED HYPERTROPHY & FAILURE

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The objective is to test the hypothesis that cardiac angiotensin At/1 receptor activation, which is opposed by the AT/2 receptor, is mandatory for the development of pressure overload hypertrophy and the later transition to failure in the intact heart. Recent studies show that the stretch-induced hypertrophic response of neonatal myocytes in vitro depends on the local release of angiotensin II and AT/1 receptor activation. In contrast, AT/2 receptor activation is postulated to counteract AT/1-mediated cell growth. We have established a model of load-induced ventricular hypertrophy with ascending aortic banding which is characterized by increased cardiac angiotensin II activation during early adaptive hypertrophy, and a well-defined later stage of transition to failure. We have made the novel observation that chronic ACE- inhibition in this model regresses myocyte hypertrophy, improves survival, and prevents the development of impaired contractile function despite persistent severe elevation of left ventricular systolic pressure relative to untreated banded animals. These data implicate but do not prove that cardiac AT/1 receptor activation is mandatory for load-induced hypertrophy and the late transition to failure in vivo. In Specific Aim 1 we will test the hypothesis that AT/1 receptor activation is required, whereas AT/2 activation inhibits, the load-induced immediate hypertrophic response of protooncogene induction and protein synthesis that we have shown in vitro in the intact isolated perfused heart. Specific Aim 2 will test the hypothesis that the cardiac molecular response to chronic pressure overload and the late transition to failure s characterized by the progressive increased expression of cardiac renin-angiotensin system genes with late counterbalancing upregulation of the "anti-growth" AT/2 receptor as measured by quantitative RT-PCR. We will exploit comparison of the pressure overloaded left ventricle which develops hypertrophy, and the adjacent right ventricle which does not. Specific 3 will test the hypothesis that chronic AT/1 receptor inhibition, but not AT/2 receptor inhibition, regresses myocyte hypertrophy, improves survival, and modifies the late transition to failure with persistent elevation of LV systolic pressure equivalent to untreated banded animals. Using now validated methodology, we will quantitate cardiac function in vivo using serial echocardiography, and LV micromanometer pressure measurements. Specific 4 will determine the cellular basis of the improvement in contractile function in chronic AT/1 receptor inhibition. Based on preliminary studies in dissociated hypertrophied myocytes using fluorescent indicators and measurements of calcium regulatory gene expression, we predict an improvement in myocyte [Ca2+]/i and pH/i regulation in association with normalized levels of Ca2+ regulatory gene expression. These integrated studies of in vivo physiology, the isolated myocyte, and cardiac gene expression, will determine if cardiac AT/1 receptor activation is mandatory for load-induced immediate hypertrophic response, and the late transition from hypertrophy to failure in vivo. These questions are fundamental to the biology of human hypertrophy and failure.