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J. Biol. Chem., Vol. 283, Issue 37, 25256-25263, September 12, 2008

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Bidirectional Actions of Hydrogen Peroxide on Endothelial Nitric-oxide Synthase Phosphorylation and Function

CO-COMMITMENT AND INTERPLAY OF Akt AND AMPK^*

From the Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Molecular and Cellular Biochemistry, The Ohio State University Medical Center, Columbus, Ohio 43210

Endothelial NO synthase (eNOS) is critically modulated by kinases via the phosphorylation of its Ser¹¹⁷⁹ (bovine) or Ser¹¹⁷⁷ (human) residue. Reactive oxygen species such as H₂O₂ was reported to activate Akt, leading to increased eNOS Ser¹¹⁷⁹ phosphorylation and activity. But reactive oxygen species are also known to attenuate eNOS function in cardiovascular diseases. Prior studies showing H₂O₂-stimulated eNOS phosphorylation were performed on serum-starved cells, and only the short term effect of H₂O₂ was examined. Here we found that the effects of H₂O₂ on eNOS Ser¹¹⁷⁹ phosphorylation and function were bidirectional. With endothelial cells cultured with serum, H₂O₂ initially raised eNOS Ser¹¹⁷⁹ phosphorylation and activity. However, after the peak increase at 30 min, eNOS Ser¹¹⁷⁹ phosphorylation dramatically declined. Parallel to the alterations of eNOS Ser¹¹⁷⁹ phosphorylation, Akt was transiently activated by H₂O₂ and subsequently became dormant. In contrast, AMP-activated protein kinase (AMPK) was progressively activated in H₂O₂-treated cells. Blocking Akt activation abolished the initial rise of eNOS Ser¹¹⁷⁹ phosphorylation after H₂O₂ treatment. In long term H₂O₂-treated cells where Akt was deactivated, significant amounts of Ser¹¹⁷⁹-phosphorylated eNOS remained. AMPK inhibition eradicated the remaining eNOS Ser¹¹⁷⁹ phosphorylation. Taken together, these studies revealed that Akt and AMPK orchestrated a bidirectional action on eNOS Ser¹¹⁷⁹ phosphorylation in H₂O₂-treated cells. Long term H₂O₂ exposure decreased eNOS Ser¹¹⁷⁹ phosphorylation, and this might account for the loss of eNOS function in cardiovascular diseases where chronic oxidative injury occurs.

Received for publication, March 28, 2008 , and in revised form, July 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants HL77575 and HL86965. 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: 605 Davis Heart and Lung Research Institute, The Ohio State University, 473 West 12th Ave., Columbus, OH 43210. Tel.: 614-292-5709; Fax: 614-292-6898; E-mail: yong.xia{at}osumc.edu.

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