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.


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.
Tanaka
Jun
J
Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA.
Qiang
Li
L
Banks
Alexander S
AS
Welch
Carrie L
CL
Matsumoto
Michihiro
M
Kitamura
Tadahiro
T
Ido-Kitamura
Yukari
Y
DePinho
Ronald A
RA
Accili
Domenico
D
D000818:Animals; D001011:Aorta / Q000201:enzymology; D001786:Blood Glucose / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000235:genetics / Q000401:mortality / Q000517:prevention & control; D018797:Cell Cycle Proteins; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000235:genetics / Q000401:mortality / Q000517:prevention & control; D004730:Endothelium, Vascular / Q000201:enzymology / Q000502:physiology* / Q000503:physiopathology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D051379:Mice; D008833:Microcirculation / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics
D001786:Blood Glucose; D018797:Cell Cycle Proteins; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C108803:FOXO4 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D008077:Lipoproteins, LDL; D014157:Transcription Factors; D012313:RNA; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III