Abstract 13913: Metabolic Stress-Induced Activation of FoxO1 Triggers Diabetic Cardiomyopathy
Introduction: Diabetic cardiomyopathy is a disorder typified by alterations in cardiac metabolism, morphology, and function independent of hypertension and coronary artery disease. We have shown previously that constitutive activation of FoxO1 or FoxO3 in cardiac myocytes results in altered Akt activation, reduced insulin sensitivity, and impaired metabolism. Based on this, we hypothesized that 1) persistent activation of FoxO contributes to myocardial insulin resistance and diabetic cardiomyopathy, and 2) cardiomyocyte-specific FoxO deletion will sustain cardiac function in the setting of metabolic stress.
Methods & Results: Echocardiography in diabetic mice (db/db and high fat diet (HFD) fed WT mice, n=8) revealed ventricular dilatation and reduced systolic function consistent with a cardiomyopathic phenotype. Myocardial insulin resistance was evidenced by a 2-fold decrease in phosphorylated (active) Akt. Nuclear extracts from both db/db and HFD hearts showed 2-fold increases in the abundance of FoxO1/3 proteins, significant decreases in phosphorylated (inactive) FoxO1/3, and increases in the mRNAs of FoxO targets. Remarkably, in both αMHC-MerCreMer;FoxO1flox/flox and αMHC-MerCreMer; FoxO1&3flox/flox (FoxO KO) mice fed a HFD (25 wks), cardiac function was maintained (%FS: 68±3, 67±4 vs 35±3, p<0.01, n=8), 60 wk-mortality was reduced (25% vs 80% cntl), cardiomyocyte cross-sectional area was reduced (263 vs 494 μ m2, p<0.05), and fetal gene expression was lowered. FoxO-mutant mice also manifested a marked shift in metabolic substrate usage to glucose from free fatty acids and reduced myocardial lipid content (1.8±0.6, 2.0±0.1 vs 5.2±1 mg/g, p<0.01) despite the presence of systemic insulin resistance. Furthermore, adult cardiac myocytes isolated from FoxO KO mice manifested sustained insulin sensitivity. In contrast, IRS1 levels were decreased in cardiomyocytes over-expressing FoxO1.
Conclusions: FoxOs are chronically active in diabetic cardiomyocytes and are required for cardiac metabolic derangements contributing to both myocardial insulin resistance and the pathogenesis of diabetic cardiomyopathy. Persistent activation of FoxO1 blunts AKT signaling through down-regulation of IRS1 activity.
- © 2011 by American Heart Association, Inc.