Several lines of evidence have suggested that growth hormone (GH), and its local effector insulin-like growth factor-l (IGF-I), promote physiological cardiac growth. GH and/or IGF-I treatment have also been demonstrated to increase myocardial contractility and cardiac output in experimental models of cardiac failure. Similarly, insulin administered with glucose and potassium (GIK therapy) can decrease the rate of ischemic cell death following acute myocardial infarction. However, the effects of GH therapy in human subjects is still inconclusive, and recent reports in animal models suggest that long-term IGF-I treatment may not be beneficial because chronic IGF-I stimulation can induce aspects of pathological hypertrophy. Therefore, the development of therapeutic strategies for maintaining cardiac function in the failing heart could benefit from a better understanding of the molecular distinction between normal cardiac growth and pathological cardiac hypertrophy. We have shown that IGF-1 and insulin activate the phosphatidylinositol 3-kinase/Akt signaling pathway in cardiac myocytes and vascular cells. We have also shown that activation of this pathway is an essential step in mediating the IGF- and insulin-induced survival and growth signals in cardiac myocytes. Therefore, this grant will focus on mechanisms of myocardial remodeling in mice that have gain-of-function or loss-of-function genetic alterations at this and subsequent signaling steps. We propose to analyze myocardial remodeling and failure in inducible Akt transgenic and knockout mouse models (Aim 1);assess coronary vasculature growth and regression during myocardial growth and regression (Aim 2);analyze the role of the Akt-regulated transcription factors in controlling heart growth and function (Aim 3);and perform genomic and proteomic analyses of Akt and forkhead-mediated remodeling in the heart (Aim 4). These studies should provide a better understanding of the mechanism that regulate adaptive and maladaptive remodeling, and provide new insights about the development and treatment of heart failure.
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