The goal of this research is to characterize the post-natal regulatory mechanisms that control heart growth and apply these findings to develop new approaches to treat heart failure. Trophic factors such as growth hormone (GH) and insulin-like growth factor (IGF) are required for normal heart development and have been shown to inhibit and reverse the progression of heart failure. The beneficial effects of GH/IGF on cardiac function are thought to originate, at least in part, from their ability to promote physiological cardiac growth. Furthermore, insulin administered with glucose and potassium (GIK therapy) can decrease the rate of ischemic cell death following acute myocardial infarction, thereby reducing patient mortality. These factors activate the phosphatidylinositol 3-kinase/Akt intracellular signaling pathway, and we have previously shown that the serine-threonine kinase Akt mediates IGF-induced survival signals in cardiac myocytes. Therefore, we hypothesize that Akt signaling is a component of cardiac hypertrophy (Aim 1). In addition, our preliminary data suggest that insulin is an important regulatory of normal post-natal cardiac growth. Together with the finding that insulin is a potent activator of Akt in cardiac myocytes, we hypothesize that insulin regulates cardiac growth during postnatal development through Akt-dependent pathways(Aim 2). We also hypothesize that activation of Akt signaling will improve heart function in models of heart failure by promoting physiological cardiomyocyte hypertrophy (Aim 3). Finally, we hypothesize that the growth-promoting and protective activities of Akt signaling are partly mediated through the regulation of a specific subset of Forkhead transcription factors (Aim 4). Akt-regulated Forkhead factors are implicated in the control of cell growth survival, but they have not been investigated with regard to their regulation and function in the heart. Collectively, the proposed study will contribute to our understanding of the mechanisms that regulate physiological and pathological cardiac growth, and will provide insight for the development of novel approaches to treat heart failure.
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