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Activation of the AMP-Activated Kinase by Antidiabetes Drug Metformin Stimulates Nitric Oxide Synthesis In Vivo by Promoting the Association of Heat Shock Protein 90 and Endothelial Nitric Oxide Synthase

¹ Vascular Research Laboratory, Department of Surgery, Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee
² Division of Endocrinology, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
³ Department of Genetics, Development and Molecular Pathology, Cochin Institute, University of Paris V, National Institute of Health and Medical Research U567, National Center of Scientific Research UMR8104, Paris, France

Address correspondence and reprint requests to Ming-Hui Zou, MD, PhD, Medicine Endocrinology, BSEB 325, Department of Medicine, University of Oklahoma Health Science Center, 941 Stanton L. Young Blvd., Oklahoma City, OK 73104. E-mail: ming-hui-zou{at}ouhsc.edu

Key Words: AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside • AMPK, 5'-AMP–activated kinase • AMPK-CA, constitutively active AMPK kinase • BAEC, bovine aortic endothelial cell • cGMP, cyclic GMP • eNOS, endothelial nitric oxide synthase • FBS, fetal bovine serum • FITC, fluorescein isothiocyanate • GFP, green fluorescence protein • hsp, heat shock protein • ICAM, intracellular adhesion molecule • L-NAME, L-nitro-arginine methyl ester • 3-NT, 3-nitrotyrosine • Ser1179, serine-1179 • SOD, superoxide dismutase • Thr172, threonine-172 • PDK, phosphoinositide-dependent kinase • VCAM, vascular cell adhesion molecule

Metformin, one of most commonly used drugs for the treatment of type 2 diabetes, improves vascular endothelial functions and reduces cardiovascular events in patients with type 2 diabetes, although its mechanisms remain unknown. The current study aimed to elucidate how metformin improves endothelial functions. Exposure of cultured bovine aortic endothelial cells (BAECs) to clinically relevant concentrations of metformin (50–500 µmol/l) dose-dependently increased serine-1179 (Ser1179) phosphorylation (equal to human Ser1179) of endothelial nitric oxide (NO) synthase (eNOS) as well as its association with heat shock protein (hsp)-90, resulting in increased activation of eNOS and NO bioactivity (cyclic GMP). These effects of metformin were mimicked or completely abrogated by adenoviral overexpression of a constitutively active 5'-AMP–activated kinase (AMPK) mutant or a kinase-inactive AMPK-, respectively. Furthermore, administration of metformin as well as 5-aminoimidazole-4-carboxamide ribonucleoside, an AMPK agonist, significantly increased eNOS Ser1179 phosphorylation, NO bioactivity, and coimmunoprecipitation of eNOS with hsp90 in wild-type C57BL6 mice but not in AMPK-1 knockout mice, suggesting that AMPK is required for metformin-enhanced eNOS activation in vivo. Finally, incubation of BAECs with clinically relevant concentrations of metformin dramatically attenuated high-glucose (30 mmol/l)–induced reduction in the association of hsp90 with eNOS, which resulted in increased NO bioactivity with a reduction in overexpression of adhesion molecules and endothelial apoptosis caused by high-glucose exposure. Taken together, our results indicate that metformin might improve vascular endothelial functions in diabetes by increasing AMPK-dependent, hsp90-mediated eNOS activation.

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