Myocardial hypertrophy, an adaptation response to hemodynamlc burden, secondary to vascular abnormalities, hypertension and valvular disease, is recognized as a major risk factor for the development of congestive heart failure. The recent experimental approaches based on cultured cardiac cells, isolated heart and genetic manipulation in animal models have allowed the identification of distinct signal transduction pathways involved in myocardial hypertrophy. However, the molecular mechanism(s) by which the cellular hypertrophy is induced and the precise role the signaling molecules play in the hypertrophic response has remained elusive. Our experiments below are designed to test the hypothesis that despite the multiplicity of the pathways involved in different aspects of hypertrophy and the diversity of induction signals, a common mechanism is at the root of cardiac hypertrophy. Our recent work with that of others has documented that activation of the Jak/Stat signal transduction pathway occurs in response to a host of hypertrophic agonists. It has also uncovered a mechanism by which the activated Jak/Stat pathway underlies mobilization of the gene activation program intrinsic to hypertrophy. The experiments outlined here seek not only to implicate the activated Jak2 to play a central role in hypertrophy but will also examine just how it links the extra-cellular signals to the mechanism by which they are transduced into long term functional response. Specifically, we will investigate (Specific aim 1) the role of constitutively activated Jak2 via adenovirus-mediated expression in cardiac cells in culture. In concert, we will examine the effects of the heart targeted Jak2 expression in transgenic mice and in pressure overload hypertrophy models. We will also investigate (Specific aim 2) whether there is a cross talk between the Jak/Stat signaling and the components of other major pathways in an in vivo context. As part of Specific aim 3, we will examine the requirements of the renin-angiotensin system and its linkage to the Jak/Stat pathway in pressure overload hypertrophy. Finally, we will produce the heart-targeted disruption of Jak2 gene in mice in an attempt to demonstrate the dependence of hypertrophy induction upon Jak2. These approaches are expected to provide a wealth of information useful in the generation of targets for drug intervention and gene-based therapy for heart failure.
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