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Role of cardiac FoxO1 in conditions of insulin resistance, nutrient excess, and diabetes Puthanveetil, Prasanth Nair

Abstract

Glucocorticoids increase PDK4 mRNA and protein expression, which phosphorylates PDH, thereby preventing the formed pyruvate from undergoing mitochondrial oxidation. This increase in PDK4 expression is mediated by the mandatory presence of FoxOs in the nucleus. Rat cardiomyocytes exposed to Dx produced a robust decrease in glucose oxidation. Measurement of FoxO compartmentalization demonstrated increase in nuclear, but resultant decrease in cytosolic content of FoxO1 with no change in the total content. The increase in nuclear content of FoxO1 correlated to an increase in nuclear phospho p38 MAPK together with a robust association between this transcription factor and kinase. Dx also promoted nuclear retention of FoxO1 through a decrease in phosphorylation of Akt, an effect mediated by heat shock proteins binding to Akt. Instead, Dx increased the association of Sirt1 with FoxO1, thereby causing a decrease in FoxO acetylation. Our data suggests that FoxO1 has a major PDK4 regulating function. Related to nutrient excess, FoxO1 has a role in regulating fatty acid (FA) uptake and oxidation, and triglyceride storage by mechanisms that are largely unresolved. We examined the mechanism behind palmitate (PA) induced TG accumulation in cardiomyocytes. PA treated cardiomyocytes showed substantial increase in TG accumulation, accompanied by amplification in nuclear migration of phospho-p38 and FoxO1, iNOS induction and translocation of CD36 to the plasma membrane. PA also increased Cdc42 protein and its tyrosine nitration, there by re-arranging the cytoskeleton and facilitating CD36 translocation. Cardiomyocyte cell death is a major contributing factor for diabetic cardiomyopathy, and multiple mechanisms have been proposed for its initiation. Diabetes increased the nuclear content of FoxO1 as a result of attenuated survival signalling. Increased nuclear FoxO1 augmented iNOS induction in the diabetic myocardium. The iNOS induced nitrosative stress increased the nitrosylation of GAPDH accompanied by its binding to Siah1 and translocation to the nucleus with an increased nuclear nitrosative stress. iNOS also nitrosylated caspase-3 there by hindering its ability to cleave PARP, a direct downstream target of Caspase-3. The resultant effect is activation of PARP with an nuclear compartmentalization of Apoptosis Inducing Factor (AIF) and resultant cell death.

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