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J. Biol. Chem., Vol. 283, Issue 17, 11210-11217, April 25, 2008

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Rosiglitazone Stimulates Nitric Oxide Synthesis in Human Aortic Endothelial Cells via AMP-activated Protein Kinase^*

James G. Boyle, Pamela J. Logan, Marie-Ann Ewart, James A. Reihill, Stuart A. Ritchie, John M. C. Connell, Stephen J. Cleland, and Ian P. Salt¹

From the The Henry Wellcome Laboratory for Cell Biology, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences and the Division of Cardiovascular and Medical Sciences, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8QQ, United Kingdom

The thiazolidinedione anti-diabetic drugs increase activation of endothelial nitric-oxide (NO) synthase by phosphorylation at Ser-1177 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 Ser-1177. 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 Ser-1177. 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 Ser-1177 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- 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.

Received for publication, December 10, 2007 , and in revised form, February 15, 2008.

^* This work was supported in part by project grants from the British Heart Foundation. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported by a Diabetes UK R. D. Lawrence fellowship. To whom correspondence should be addressed: The Henry Wellcome Laboratory for Cell Biology, Division of Biochemistry and Molecular Biology, Davidson Bldg., Inst. of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. Tel.: 44-141-3302049; Fax: 44-141-3304620; E-mail: i.salt{at}bio.gla.ac.uk.

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