Regulation of Cardiac Growth by Akt-FoxO Signaling

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The molecular mechanisms that control cardiomyocyte proliferation and growth are fundamental to normal heart development, and dysregulation of these processes contributes to congenital and adult cardiac disease. During prenatal development, the heart grows mainly through hyperplastic growth of differentiated cardiomyocytes, and increased sarcomeric architecture is apparent as development proceeds. Postnatally, cardiomyocytes withdraw from the cell cycle, and heart growth is due largely to cardiomyocyte hypertrophy. The regulatory mechanisms that control differential regulation of proliferation and hypertrophy during development and that control perinatal cardiomyocyte cell cycle withdrawal are not completely known. In skeletal and smooth muscle, FoxO transcription factors antagonized by Akt phosphorylation directly regulate expression of genes that inhibit cell cycle progression and promote muscle atrophy. The functions of the Akt signaling pathway and FoxO transcription factors in the developing heart will be examined in embryonic, fetal, neonatal and adult cardiomyocytes in cell culture and in genetically manipulated mouse models. The hypothesis is that Akt-mediated inactivation of FoxO transcription factors promotes cardiomyocyte proliferation and regulates heart growth during development. Preliminary studies demonstrate that FoxO are expressed in the developing heart, and treatment of fetal cardiomyocytes with IGF-I leads to increased proliferation and FoxO1 phosphorylation through a PI3K-dependent mechanism. Aim 1. Determine if FoxO1 or FoxOS regulate proliferation and maturation downstream PI3K/AKT signaling in cultured embryonic, fetal or neonatal cardiomyocytes. Aim 2. Determine if FoxO1 regulates differential growth and hypertrophy of the developing myocardium in vivo. The immediate goal is to determine if FoxO transcription factors regulated by Akt phosphorylation control cardiomyocyte proliferation and cell size (hypertrophy) at specific stages of cardiomyocyte development and maturation. The long term goal is to define signal transduction mechanisms underlying growth, differentiation and maturation of the developing and adult myocardium. These studies are designed to reveal developmentally important growth control mechanisms of cardiac muscle that could be exploited in the treatment of congenital or adult heart disease.