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Diabetes. 2009 Oct;58(10):2344-54. doi: 10.2337/db09-0167. Epub 2009 Jul 7.

Foxo1 links hyperglycemia to LDL oxidation and endothelial nitric oxide synthase dysfunction in vascular endothelial cells.

Author information

1
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA.

Abstract

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 Foxo1 in vascular endothelial cells.

RESULTS:

Foxo1 promotes inducible NOS (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, 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 proatherogenic changes in vascular endothelial cell function.

PMID:
19584310
PMCID:
PMC2750207
DOI:
10.2337/db09-0167
[Indexed for MEDLINE]
Free PMC Article

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