The atrial natriuretic peptide (ANP) is a cardiac hormone which is produced predominantly, though not exclusively, in the atria of the heart. The biological activity of ANP including its vasorelaxant, natriuretic, diuretic, and aldosterone-, renin- and vasopressin-suppressant properties suggest that this peptide represents an endogenous anti-hypertensive hormone antagonizing factors which act to increase intravascular volume and arterial blood pressure. The present proposal will be directed towards the identification and characterization of hormonal, autocrine or paracrine factors which regulate the synthesis and secretion of this peptide. Particular attention will be devoted to those factors with well-documented activity in the cardiovascular system and to the mechanism whereby stretch, or tension, activates ANP gene transcription. The latter question will be approached using novel in vitro system to develop tension on the surface of a cell culture plate. Once we have identified the relevant regulatory factors we will attempt to define the locus of their activity at a molecular level. Agonist-sensitive cis-acting DNA elements will be identified using standard DNA transfection analyses of chimeric gene constructions while relevant transacting nuclear proteins involved in mediating the agonist-specific effect will be identified using gel mobility shift analysis and DNAse I protection studies. Findings obtained with these studies will then be compared with those obtained using cardiocytes from genetically hypertensive rats. Key differences might suggest a role for ANP gene malregulation in the pathogenesis of these heritable forms of hypertension. Finally, using a transgenic line of mice bearing atrial rhabdomyosarcomas, we will attempt to generate an in vivo model of chronic, inappropriate ANP excess. We will also use this tumor tissue as a source of material to generate a continuous cell line of ANP-producing cardiac myocytes. Taken together the information generated from these studies should provide valuable insights into the regulation of this important cardiovascular peptide and its potential role in the pathogenesis of essential hypertension. It should also provide some highly novel information regarding the linkage of stretch-induced signals to the cellular transcriptional machinery.
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