REGULATION OF CARDIAC HYPERTROPHY BY ANGIOTENSINS

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The renin angiotensin system has a major role in the regulation of cardiovascular, renal and endocrine functions. Angiotensin II can activate intracellular responses including calcium mobilization, stimulation of sodium/hydrogen exchange, inositol phosphate metabolism, diacylglycerol production, protein kinase C, Raf-1 kinase hyperphosphorylation, the mitogen-activated protein kinase cascade, phosphorylation of nuclear lamina and transcriptional regulation of immediate and intermediate response genes. Recent published data support the concept that this peptide plays an important role in the compensatory left ventricular hypertrophy that occurs in association with pressure overload and in ventricular remodeling following myocardial infarction. Our data, obtained in both in vitro and in vivo experimental models, suggest that there is an intracardiac renin angiotensin system, which may contribute to these responses. Recent in vitro data indicate that stimulation of various signal transduction pathways and growth, in response to static stretch, may be mediated by local production and release of angiotensin II. We will test the hypotheses that the intracardiac renin angiotensin system is regulated by mechanical stretch and humoral stimuli and that activation of the intracardiac renin angiotensin system is a prerequisite for the development of cardiac hypertrophy in vivo. Regulation will be defined in an in vitro cell culture model using mechanical and humoral stimuli and in vivo using experimental models of pressure overload and myocardial infarction. Regulated components of the renin angiotensin system will be determined using pharmacological inhibitors; neutralizing antibodies; radioimmunoassay; radiolabeled receptor binding; quantitative, multiplex, reverse transcriptase polymerase chain reaction; in situ hybridization; and immunohistochemical analyses. The contribution of individual renin angiotensin system components will be determined utilizing gene transfer technology. Determining the importance of, and mechanisms by which an intracardiac renin angiotensin system is regulated has significant implications for understanding the biological role of this system in association with developmental, physiological and pathological processes. These directions have the broader application of contributing to the successful management of cardiovascular disease.