Abstract 14042: FoxO1 Ablation Rescues Metabolic Stress-induced Cardiac Remodeling
Introduction: Diabetic cardiomyopathy is typified by alterations in cardiac metabolism, morphology, and function independent of hypertension and coronary artery disease. We have shown previously that metabolic stress-induced activation of FoxO1 contributes to lipotoxicity, insulin resistance, and diabetic cardiomyopathy, and that cardiomyocyte-specific FoxO1 ablation preserves insulin responsiveness and prevents diabetic cardiomyopathy. Here, we set out to define mechanisms whereby FoxO1 contributes to diabetic cardiomyopathy.
Methods & Results: In a time course analysis, we found that mice (n=5) fed a high fat diet (HFD) for 2 wk manifested a ~3-fold (p<0.05) reduction in cardiac insulin sensitivity that correlated with cardiomyocyte FoxO1 nuclear localization and activation; each of these events preceded development of contractile dysfunction or fetal gene activation. FoxO1 gain- and loss-of-function analyses in cultured neonatal rat ventricular cardiomyocytes (NRVMs) confirmed that FoxO1-dependent down-regulation of IRS1 is associated with activation of mTOR, JNK, and PDK4, similar to that observed in mice exposed to short-term HFD. Additionally, inhibition of mTOR (Torin), JNK (SP600125), or PDK4 (DCA, siRNA) restored IRS1 protein abundance in NRVMs expressing a constitutively active FoxO1 mutant. Remarkably, silencing FoxO1 following development of substantial contractile dysfunction in αMHC-MerCreMer;FoxO1flox/flox mice (HFD 20 wks) rescued contractile performance, reduced cardiomyocyte cross-sectional area, decreased fibrosis, enhanced glucose uptake, diminished cardiomyocyte lipid accumulation, and improved insulin sensitivity, all in association with diminished activation of mTOR, JNK, and PDK4.
Conclusions: Metabolic stress-induced nuclear localization of FoxO1 precedes emergence of ventricular hypertrophy, contractile dysfunction, and insulin resistance. FoxO1-triggered IRS1 degradation is mediated by a signaling circuit that involves PDK4, mTOR, and JNK. Finally, cardiomyocyte-specific silencing of FoxO1 is capable of reversing significant elements of HFD-induced pathological cardiac remodeling.
- © 2013 by American Heart Association, Inc.