In response to various hormonal, genetic, and mechanical stimuli, the myocardium adapts to increased workloads through the hypertrophy of individual muscle cells. The hypertrophic response of the myocardium can be divided into several widely accepted phenotypic features of hypertrophy, including: 1)an increase in myocardial cell size without an accompanying proliferative response; 2) an increase in contractile protein content of individual myocardial cells; 3) activation of ANF synthesis and its release from hypertrophied ventricular cells; 4) activation of the expression of embryonic marker proteins and contractile protein isoform switching; 5) induction of proto-oncogenes and other members of the immediate early gene program; and 6) activation of cardiac gene transcription. While each of these phenotypic characteristics of hypertrophy have been carefully documented in both in vivo and cellular models of hypertrophy, surprisingly little is known regarding the precise signaling mechanisms which are causally related to the development of these specific features of the hypertrophic response of atrial and ventricular myocardial cells. Through coupling new advances in molecular and genetic technologies with well characterized cultured cell models and a new in vivo mouse model of hypertrophy, the central scientific theme of the Program is to identify the molecular and signaling mechanisms which activate specific features of the hypertrophic response of atrial and ventricular myocardial cells. The specific objectives are as follows: 1) To determine the role of protein kinase C and Ca++ dependent pathways in the acquisition of specific features of atrial and ventricular cell hypertrophy; 2) To determine the role of secretory and constitutive pathways for ANF synthesis hypertrophy; 3) To determine the role of cardiac specific elements, known inducible regulatory elements (serum response elements, cyclic AMP response elements, AP1, and AP-2) and the potential role of new inducible elements in the activation of MLC-2 and ANF gene activation during myocardial cell hypertrophy; 4) To determine if diverse stimuli for myocardial cell hypertrophy (pressure overload, catecholamines, and endothelia) induce distinct subsets of the immediate early gene program, and to critically examine their role in the induction of cardiac target genes and other features of the cardiac hypertrophic response; 5) To determine if diverse stimuli (pressure overload, catecholamines, and endothelia) converge on similar sets of cis regulatory elements to activate the expression of MLC-2 and ANF genes.
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