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)
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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 > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| 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 |
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