Abstract

Objective– Atherosclerotic cardiovascular disease is the leading cause of death among diabetics. Generation of oxidized low-density lipoproteins (oxLDL) and reduced nitric oxide (NO) availability due to eNOS dysfunction are critical events in atherosclerotic plaque formation. But the biochemical mechanism leading from hyperglycemia to oxLDL formation and eNOS dysfunction is unknown.

Research design and methods– Here we show that glucose, acting through oxidative stress, activates the transcription factor Foxo1 in vascular endothelial cells.

Results– Foxo1 promotes iNOS-dependent NO-peroxynitrite generation, which leads in turn to LDL oxidation and eNOS dysfunction. We demonstrate that Foxo1 gain-of-function mimics the effects of hyperglycemia on this process, while 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 proatherogenic changes in vascular endothelial cell function.