Foxo1 Links Hyperglycemia to LDL Oxidation and Endothelial Nitric Oxide Synthase Dysfunction in Vascular Endothelial Cells
- Jun Tanaka1,
- Li Qiang1,
- Alexander S. Banks1,
- Carrie L. Welch1,
- Michihiro Matsumoto1,
- Tadahiro Kitamura2,
- Yukari Ido-Kitamura2,
- Ronald A. DePinho3 and
- Domenico Accili1
- 1Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York;
- 2Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan;
- 3Center for Applied Cancer Science, Departments of Medical Oncology, Medicine and Genetics, and Belfer Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
- Corresponding author: Domenico Accili, da230{at}columbia.edu.
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.
Footnotes
-
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
- Received February 10, 2009.
- Accepted June 23, 2009.
- © 2009 by the American Diabetes Association.
