MAP Kinase and AKT Signaling in Congestive Heart Failure

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Cardiac hypertrophy and congestive heart failure are common human ailments that may develop as a consequence of abnormal signaling pathway activation involving the Akt/Protein Kinase B family. The main aim of this proposal is to investigate the role of individual Akt family members in the growth and metabolism of cardiac myocytes. Although Akt1 and Akt2 are highly homologous and are expressed at near-equal amounts in cardiac myocytes, we hypothesize that Akt1 selectively regulates physiologic myocyte growth and that Akt2 selectively regulates myocyte glucose metabolism. Preliminary data shows that Akt1, but not Akt2, may be required for the development of physiologic hypertrophy in response to insulin-like growth factor 1 (IGF-1) stimulation of cultured cardiac myocytes or in response to growth hormone-IGF-1 infusion in mice. Furthermore, initial experiments suggest that Akt1 is not required for pressure overload-induced cardiac hypertrophy, and that Akt2, but not Akt1, is required for insulin-stimulated glucose uptake in cultured cardiac myocytes. In this proposal, the relative functions of Akt1, Akt2, and Akt3 in the growth and survival of cultured neonatal rat and adult murine cardiac myocytes will be evaluated. Second, the role of Akt1 and Akt2 in the growth and contractile function of the in vivo heart will be investigated. aktT'', akt1+/~, aktz'', aW2+/", and wild type mice, currently available in our mouse colony, will be subjected to pressure overload by transverse aortic constriction and to swimming exercise training. Third, the role of Akt family members in the regulation of cardiac metabolism will be examined by ex vivo working heart analysis and by in vivo micro-positron emission tomography studies of aWfA and aM2"A mice. Finally, the ability of Akt2 and Peroxisome-Proliferator Activated Receptor a (PPARa) to regulate cardiac metabolism in a mutually antagonistic manner will be examined. Our findings will help to identify specific signaling mechanisms involved in the regulation of cardiac myocyte growth and metabolism.