Foxo1 Links Hyperglycemia to LDL Oxidation and Endothelial Nitric Oxide Synthase Dysfunction in

OBJECTIVE—Atherosclerotic cardiovascular disease is the leading cause of death among people with diabetes. Generation of oxidized LDLs and reduced nitric oxide (NO) availability because of endothelial NO synthase (eNOS) dysfunction are critical events in atherosclerotic plaque formation. Biochemical mechanism leading from hyperglycemia to oxLDL formation and eNOS dysfunction is unknown. RESEARCH DESIGN AND METHODS—We show that glu-cose, acting through oxidative stress, activates the transcription factor Foxo1 in vascular endothelial cells. RESULTS—Foxo1 promotes inducible NOS (iNOS)-dependent NO-peroxynitrite generation, which leads in turn to LDL oxida-tion and eNOS dysfunction. We demonstrate that Foxo1 gain-of-function mimics the effects of hyperglycemia on this process, whereas conditional Foxo1 knockout in vascular endothelial cells prevents it. CONCLUSIONS—The findings reveal a hitherto unsuspected role of the endothelial iNOS-NO-peroxynitrite pathway in lipid peroxidation and eNOS dysfunction and suggest that Foxo1 activation in response to hyperglycemia brings about proathero-genic changes in vascular endothelial cell function. Diabetes 58: 2344–2354, 2009 Cardiovascular disease (CVD) is the leadingcause of death of diabetic patients. Type 2diabetes increases CVD-related morbidity andmortality by two- to fourfold (1). Unlike micro-vascular diabetes complications, the benefit of tight glycemic control on the prevention of macrovascular complications remains unclear (2), owing possibly to the contribution of insulin resistance as an independent risk factor (3,4). A growing consensus indicates that the adverse effects of hyperglycemia on diabetes complications are exerted through a shared pathway of oxidative stress, leading to oxidative modification of lipid, protein, and DNA; activa-tion of proinflammatory pathways; DNA damage; and cellular apoptosis (5). In contrast, the effects of “insulin resistance ” are heterogeneous, primarily because the con-stellation of events commonly subsumed under this mon-iker is indeed an admixture of insulin resistance and excessive insulin sensitivity, at the cellular and organ leve