Abstract 15865: Persistent Activation of FoxO Contributes to Insulin Resistance and Diabetic Cardiomyopathy
Introduction: Insulin resistance in the myocardium is a hallmark feature of numerous forms of heart disease, and cardiomyopathy is prevalent in diabetic patients. Previous work has demonstrated that sustained activation of FoxO1 or FoxO3 in cardiac myocytes results in altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism. Based on this, we hypothesized that 1) persistent activation of FoxO contributes to myocardial insulin resistance and diabetic cardiomyopathy, and 2) mice engineered with cardiomyocyte-specific FoxO inactivation will manifest preserved cardiac function in the setting of dietary challenge.
Methods and Results: Echocardiography in 12 week old diabetic mice (db/db) revealed ventricular dilatation (systole: 1.21±0.02mm, n=5 vs 0.59±0.05, cntl, n=6, p<0.01; diastole: 2.9±0.2 vs 2.1±0.2 mm, p<0.05) and reduced systolic function (% Fractional Shortening, FS: 48±3 vs 71±3, p<0.05) consistent with a cardiomyopathic phenotype. Myocardial insulin resistance was evidenced by a 2-fold decrease in phosphorylated (active) Akt. Compared with controls, no differences were found in the total cellular abundances of FoxO1/3 proteins. However, we detected significant decreases in the abundance of phosphorylated (inactive) FoxO1/3 and increases in the mRNA levels of FoxO targets p21 and MuRF-1, consistent with FoxO hyperactivation. To test the necessity of FoxO, we studied cardiomyocyte-specific, conditional FoxO knockouts (n=6–8). Remarkably, in both αMHC-MerCreMer;FoxO1flox/flox and αMHC-MerCreMer;FoxO1&3flox/flox (FoxO KO) mice fed a western diet (60% fat for 25 wks) cardiac function was maintained (%FS: 68±3, 67±4 vs 35±3%, p<0.01) and myocardial lipid content was reduced (1.8±0.6, 2.0±0.1 vs 5.2±1 mg/g, p<0.01). Furthermore, cardiac myocytes isolated from FoxO KO mice exposed to exogenous insulin (100nM) manifested sustained and increased insulin sensitivity (increased p-Akt at 0, 2, 5, 60 min) compared with western diet-fed controls.
Conclusions: These data lend additional strong support to a model where FoxO factors are persistently and inappropriately active in cardiomyocytes in diabetic animals, contributing to both insulin resistance and pathogenesis of diabetic cardiomyopathy.
- © 2010 by American Heart Association, Inc.