Atrial natriuretic factor (ANF) plays a critical role in the maintenance of blood pressure and sodium balance in both normal and hypertensive states. ANF may also play an important role in the pathophysiology of hypertension. In normal physiological circumstances, ANF is expressed almost exclusively in the atrium. During periods of sustained increases in blood pressure and associated compensatory hypertrophy, such as in genetic models of spontaneous hypertension and related conditions of pressure and volume overload, the expression of ANF is induced within ventricular myocardial cells. Ventricular cells express the ANF gene early in the embryonic state, which is extinguished during normal adult development. Thus, the anomalous expression of ANF within ventricular myocardial cells may be representative of the reinduction of embryonic genes which is a feature of the cardiac hypertrophic response and might be viewed as a compensatory mechanism which is activated during periods of increased arterial pressure or volume overload. In the setting of hypertensive cardiomyopathy and other forms of LV dilatation, the circulating levels of ANF are significantly increased, accompanied by the expression of ANF and the induction of ANF mRNA in ventricular cells. Accordingly, ventricular cells represent an important source for ANF in the setting of chronic hypertension and associated cardiac hypertrophy. The mechanisms which regulate the induction of expression of ANF in the hypertrophied ventricle are unknown. One of the major difficulties in studying this problem has been the lack of an appropriate ventricular cell model to study the expression of ANF during the onset of hypertrophy. The present proposal will couple currently available antibodies, cDNA probes, promoters, and expression vectors to a cultured ventricular myocardial cell system in which a several-fold induction of ANF release and ANF mRNA levels are observed during hypertrophy of cells induced by stimulation with either alpha adrenergic agonists or endothelin-1. Accordingly, the Specific Aims of the present proposal are four-fold: 1) to determine the role of transcriptional versus post-transcriptional mechanisms for the induction of ANF mRNA following alpha adrenergic stimulation; 2) to identify the cis acting sequences within the rat ANF gene which regulate inducibility following alpha adrenergic stimulation ; 3) to determine the role of the induction of c-fos, c- jun, and the putative transcriptional factor, Egr- 1 in the induction of ANF gene expression; 4) to determine if endothelin and a adrenergic stimulation activate ANF gene expression through similar cis regulatory elements. These studies will increase our understanding of the mechanisms which govern the induction of ANF gene expression in ventricular cells, and may also add insight into the mechanisms which lead to ANF induction in the setting of cardiac hypertrophy.
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