Myocardial ventricular cell hypertrophy is an important component of many genetic and acquired disease states such as hypertension, heart failure, and valvular heart disease. Many characteristics of hypertrophy have been well documented in both in vitro culture systems and in vivo models of pressure overload hypertrophy. These characteristics include an induction of immediate early genes, and an induction of ANF gene expression, a marker of a program of embryonic gene expression. The precise molecular signaling mechanisms which induce this program of embryonic gene expression during ventricular cell hypertrophy are poorly characterized. In order to address the complex regulatory mechanisms associated with the expression of these embryonic genes, the long term goal of this project is to utilize molecular and cellular approaches to carefully analyze the cis elements and trans acting factors that may be important in the regulation of ANF gene expression during ventricular cell hypertrophy. Utilizing a well characterized model of adrenergically induced ventricular cell hypertrophy in cultures, and a recently described in vivo transient assay of gene expression combined with a murine model of transverse aortic constriction, we propose the following: 1) To characterize the precise cis regulatory elements which mediate the inducibility of the ANF gene during alpha adrenergic and endothelin induced hypertrophy of cultured neonatal rat ventricular myocardial cells; 2) To identify the trans acting factors which mediate ventricular cell hypertrophy in the in vitro models; 3) To characterize cis elements which mediate the inducibility of the ANF gene in an in vivo model of pressure overload ventricular cell hypertrophy. The results of these studies should lead to improved understanding of the transcriptional mechanisms which mediate inducible expression of the ANF gene during ventricular cell hypertrophy.
