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172 ACTIVATION OF THE ADENOSINE MONOPHOSPHATE-ACTIVATED KINASE BY THE ANTIDIABETES DRUG METFORMIN IMPROVES NITRIC OXIDE BIOACTIVITY IN VIVO.
  1. B. J. Davies,
  2. Z. Xie,
  3. M. -H. Zou
  1. Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK

Abstract

Metformin, one of the most commonly used drugs for the treatment of type II diabetes, improves vascular endothelial functions and reduces cardiovascular events in patients with type II diabetes although its mechanisms remain unknown. The present study was aimed to elucidate how metformin improves endothelial functions. Exposure of cultured bovine aortic endothelial cells to clinically relevant concentrations of meformin (50 to 500 μM) dose-dependently increased the serine 1179 phosphorylation (equal to human serine 1177) of eNOS as well as its association with heat shock protein (hsp) 90, resulting in increased activation of eNOS and NO bioactivity (cyclic GMP, cGMP). These effects of metformin were mimicked or completely abrogated by adenoviral overexpression of a constitutively active AMP-activated kinase (AMPK) mutant or a kinase-inactive AMPKa, respectively. Further, administration of metformin as well as AICAR, an AMPK agonist, significantly increased eNOS serine 1179 phosphorylation, NO bioactivity, and co-immunoprecipitation of eNOS with hsp-90 in the wild-type C57BL6 mice but not AMPK-a1 knockout mice, suggesting that AMPK is required for metformin-enhanced eNOS activation in vivo. Finally, incubation of BAEC with clinically relevant concentrations of metformin dramatically attenuated high glucose (30 mM)-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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