SIGNALING MECHANISMS GOVERNING CARDIAC HYPERTROPHY

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DESCRIPTION: (Adapted from the Investigator's Abstract) Pressure overload induced cardiac hypertrophy is a common cause of heart failure. Despite this, the signaling pathways which mediate the development of hypertrophy in vivo are unclear. The PI has shown that blocking activation of the stress-activated protein kinases (SAPKs) by adenovirus mediated gene transfer of a dominant inhibitory mutant, SEK-1(KR), abrogated the hypertrophic response of cardiomyocytes in vitro. Most importantly, the PI has found that gene transfer of SEK-1(KR) to rat myocardium significantly inhibited pressure overload cardiac hypertrophy, suggesting that the SAPKs are critical to the hypertrophic response in vivo. The goal of this proposal is to determine the role of the SAPK pathway and a signaling pathway previously not known to play a role in the hypertrophic response, the glycogen synthase kinase-3 (GSK-3) pathway, in the development of cardiac hypertrophy in vivo. The Specific Aims include: 1. Determine the role of the SAPK pathway in the development of pressure overload cardiac hypertrophy in vivo. The preliminary data suggest that the SAPKs are critical to the development of pressure overload hypertrophy. They will complete these studies which use gene transfer of SEK-1(KR) in rat heart to block pressure overload hypertrophy. 2. Determine the role of GSK-3 in the hypertrophic response of cardiomyocytes. It is clear that there are redundant pathways signaling hypertrophy which can, in part, compensate for the loss of SAPK signaling. One of these is likely to be the calcineurin/NF-AT3 pathway. This pathway is negatively regulated by GSK-3 in T cells, but the role of GSK-3 is an important mechanism whereby cardiomyocytes amplify the hypertrophic response. 3. Determine whether modulation of GSK-3 activity alters the hypertrophic response in vivo. They will use adenovirus-mediated gene transfer of constitutively active or dominant negative GSK-3 beta to determine the role of the pathway in pressure overload hypertrophy. These studies will provide for better understanding of the pathways regulating hypertrophy in vivo, and to identify those pathways which could be targets for novel therapeutic strategies to prevent cardiac hypertrophy in patients.