Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase

Boyle, J. G., Logan, P. J., Ewart, M.-A., Reihill, J. A., Ritchie, S. A., Connell, J. M.C., Cleland, S. J. and Salt, I. P. (2008) Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase. Journal of Biological Chemistry, 283(17), pp. 11210-11217. (doi:10.1074/jbc.M710048200)

Full text not currently available from Enlighten.

Publisher's URL: http://dx.doi.org/10.1074/jbc.M710048200

Abstract

The thiazolidinedione anti-diabetic drugs increase activation of endothelial NO synthase by phosphorylation at Ser1177 and increase NO bioavailability, yet the molecular mechanisms that underlie this remain poorly characterized. Several protein kinases, including AMP-activated protein kinase, have been demonstrated to phosphorylate endothelial NO synthase at Ser1177. In the current study we determined the role of AMP-activated protein kinase in rosiglitazone-stimulated NO synthesis. Stimulation of human aortic endothelial cells with rosiglitazone resulted in the time- and dose-dependent stimulation of AMP-activated protein kinase activity and NO production with concomitant phosphorylation of endothelial NO synthase at Ser1177. Rosiglitazone stimulated an increase in the ADP/ATP ratio in endothelial cells and LKB1 was essential for rosiglitazone-stimulated AMPK activity in HeLa cells. Infection of endothelial cells with a virus encoding a dominant negative AMP-activated protein kinase mutant abrogated rosiglitazone-stimulated Ser1177 phosphorylation and NO production. Furthermore, the stimulation of AMP-activated protein kinase and NO synthesis by rosiglitazone was unaffected by the peroxisome proliferator-activated-receptor-[gamma] inhibitor, GW9662. These studies demonstrate that rosiglitazone is able to acutely stimulate NO synthesis in cultured endothelial cells by an AMP-activated protein kinase-dependent mechanism, likely to be mediated by LKB1.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Boyle, Dr James and Logan, Dr Pamela Jane and Ewart, Dr Marie-Ann and Salt, Dr Ian and Reihill, Mr James and Connell, Professor John and Cleland, Dr Stephen and Ritchie, Dr Stuart
Authors: Boyle, J. G., Logan, P. J., Ewart, M.-A., Reihill, J. A., Ritchie, S. A., Connell, J. M.C., Cleland, S. J., and Salt, I. P.
Subjects:Q Science > QR Microbiology
Q Science > QD Chemistry
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Biological Chemistry
Journal Abbr.:J Biol Chem.
Publisher:American Society for Biochemistry and Molecular Biology, Inc.
ISSN:0021-9258
ISSN (Online):1083-351X
Published Online:26 February 2008

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
392521Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
392522Regulation of aldosterone and cortisol synthesis in hypertension and cardiovascular diseaseEleanor DaviesMedical Research Council (MRC)G0400874Institute of Cardiovascular and Medical Sciences
379881The role of Tumour Necrosis Factor-alpha and Adiponectin in insulin-stimulated endothelial nitric oxide productionStuart RitchieMedical Research Council (MRC)G84/6589Cardiovascular Science