FOXO1 contributes to diabetic cardiomyopathy via inducing imbalanced oxidative metabolism in type 1 diabetes

Abstract

Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non-obese insulin-deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over-activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1-selective inhibitor AS1842856 was administered to streptozotocin-induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non-diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P