The impact of FOXO-1 to cardiac pathology in diabetes mellitus and diabetes-related metabolic abnormalities

Diabetic heart pathology has a serious social impact due to high prevalence worldwide and significant mortality/invalidation of diabetic patients suffered from cardiomyopathy. The pathogenesis of diabetic and diabetes-related cardiomyopathy is associated with progressive loss and impairment of cardiac function due to adverse effects of metabolic, prooxidant, proinflammatory, and pro-apoptotic stress factors. In the adult heart, the transcriptional factor forkhead box-1 (FOXO-1) is involved in maintaining cardiomyocytes in the homeostatic state and induction of their adaptation to metabolic and pro-oxidant stress stimuli. Insulin inhibits cardiac FOXO-1 expression/activity through the IRS1/Akt signaling in order to prevent gluconeogenesis. In diabetes and insulin resistance, both insulin production and insulin-dependent signaling is weakened or absent. Indeed, FOXO-1 becomes overproduced/overactivated in response to stress stimuli. In diabetic cardiac tissue, FOXO-1 overactivity induces the metabolic switch from the glucose uptake to the predominant lipid uptake. FOXO-1 limits mitochondrial glucose oxidation by stimulation of pyruvate dehydrogenase kinase 4 (PDK4) and increases the lipid uptake through up-regulation of surface expression of CD36. In cardiac muscle cells, lipid accumulation leads to lipotoxicity via increased lipid oxidation, oxidative stress, and cardiomyocyte apoptosis. Indeed, cardiac FOXO-1 levels and activity should be strictly regulated. FOXO-1 deregulation (that is observed in the diabetic heart) causes detrimental effects that finally lead to heart failure.