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J. Biol. Chem., Vol. 283, Issue 41, 27452-27461, October 10, 2008

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Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells^*

From the Division of Endocrinology and Diabetes, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104

In endothelial cells, the AMP-activated protein kinase (AMPK) is stimulated by sheer stress or growth factors that stimulate release of nitric oxide (NO). We hypothesized that NO might act as an endogenous activator of AMPK in endothelial cells. Exposure of human umbilical vein endothelial cells (HUVECs) to NO donors caused an increase in phosphorylation of both Thr-172 of AMPK and Ser-1177 of endothelial nitric oxide synthase, a downstream enzyme of AMPK. NO-induced activation of AMPK was not affected by inhibition of LKB1, an AMPK kinase. In contrast, inhibition of calcium calmodulin-dependent protein kinase kinase abolished the effect of NO in HUVECs. NO-induced AMPK activation in HeLa S3 cells was abolished by either 1H-(1,2,4)-oxadiazole[4,3-a]quinoxalon-1-one, a potent inhibitor for guanylyl cyclase, or 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester) (BAPTA-AM), an intracellular Ca²⁺ chelator, indicating that NO-induced AMPK activation is guanylyl cyclase-mediated and calcium-dependent. Exposure of HUVECs or isolated mice aortas to either calcium ionophore A23187 [GenBank] or bradykinin significantly increased AMPK Thr-172 phosphorylation, which was abolished by N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Finally, A23187 [GenBank] - or bradykinin-enhanced AMPK activation was significantly greater in aortas from wild type mice than those in the aortas of endothelial nitric oxide synthase knock-out mice. Taken together, we conclude that NO might act as an endogenous AMPK activator.

Received for publication, April 3, 2008 , and in revised form, August 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL079584, HL080499, HL074399, and HL089920 (to M.H.-Z.). This work was also supported by a research award from the American Diabetes Association, a research award from the Juvenile Diabetes Research Foundation, a grant from the Oklahoma Center for the Advancement of Science and Technology, and funds from the Paul H. Doris Eaton Travis Chair in Endocrinology of the University of Oklahoma Health Sciences Center (to M.H.-Z.), and this work was supported in part by a Scientist Development Grant from the American Heart Association (to Z. X.). 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, Division of Endocrinology and Diabetes, Dept. of Medicine, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Blvd., OK City, OK 73104. Tel.: 405-271-3974; Fax: 405-271-3973; E-mail: ming-hui-zou{at}ouhsc.edu.

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