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

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 glucose, acting through oxidative stress, activates the transcription factor Foxol in vascular endothelial cells. RESULTS-Foxol promotes inducible NOS (iNOS)-dependent NO-peroxynitrite generation, which leads in turn to LDL oxidation and eNOS dysfunction. We demonstrate that Foxol gain-of-function mimics the effects of hyperglycemia on this process, whereas conditional Foxol 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 Foxol activation in response to hyperglycemia brings about proatherogenic changes in vascular endothelial cell function. Diabetes 58: 2344-2354, 2009