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J. Biol. Chem., Vol. 283, Issue 29, 20186-20197, July 18, 2008

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Reactive Nitrogen Species Is Required for the Activation of the AMP-activated Protein Kinase by Statin in Vivo^*

Hyoung Chul Choi, Ping Song, Zhonglin Xie, Yong Wu, Jian Xu, Miao Zhang, Yunzhou Dong, Shuangxi Wang, Kai Lau^¶, and Ming-Hui Zou¹

From the Sections of Endocrinology and ^¶Nephrology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104 and the Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 705-717, Korea

The AMP-activated protein kinase (AMPK) is reported to mediate the beneficial effects of statin on the vascular functions, but the biochemical mechanisms are incompletely understood. The aim of the study was to determine how statin activates AMPK. Exposure of confluent bovine aortic endothelial cells to simvastatin (statin) dose-dependently increased phosphorylation of AMPK at Thr¹⁷² and activities of AMPK, which was in parallel with increased detection of both LKB1 phosphorylation at Ser⁴²⁸ and LKB1 nuclear export. Furthermore, statin treatment was shown to increase protein kinase C (PKC)- activity and PKC- phosphorylation at Thr⁴¹⁰/Thr⁴⁰³. Consistently, inhibition of PKC- either by pharmacological or genetic manipulations abolished statin-enhanced LKB1 phosphorylation at Ser⁴²⁸, blocked LKB1 nucleus export, and prevented the subsequent activation of AMPK. Similarly, in vivo transfection of PKC--specific small interfering RNA in C57BL/6J mice significantly attenuated statin-enhanced phosphorylation of AMPK-Thr¹⁷², acetyl-CoA carboxylase (ACC)-Ser⁷⁹, and LKB1-Ser⁴²⁸. In addition, statin significantly increased reactive oxygen species, whereas preincubation of mito-TEMPOL, a superoxide dismutase mimetic, abolished statin-enhanced phosphorylation of both AMPK-Thr¹⁷² and ACC-Ser⁷⁹. Finally, in vivo administration of statin increased 3-nitrotyrosine and the phosphorylation of AMPK and ACC in C57BL/6J mice but not in mice deficient in endothelial nitric-oxide synthase. Taken together, our data suggest that AMPK activation by statin is peroxynitrite-mediated but PKC--dependent.

Received for publication, April 21, 2008 , and in revised form, May 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL079584, HL080499, HL07439, and HL089220. This work was also supported by a grant from the Juvenile Diabetes Research Foundation, a grant from the Oklahoma Center for the Advancement of Science and Technology, a grant-in-aid from the American Diabetes Association, and funds from the Travis Endowed Chair in Endocrinology at the University of Oklahoma Health Science Center. A portion of the present study was presented at the annual meeting of the American Heart Association held in Orlando, Florida, in November 2007. 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.

¹ To whom correspondence should be addressed: BSEB 325, Section of Endocrinology and Diabetes, Dept. of Medicine, University of Oklahoma Health Science Center, Oklahoma City, OK 73104. Tel.: 405-271-3974; Fax: 405-271-3973; E-mail: ming-hui-zou{at}ouhsc.edu.

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