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J. Biol. Chem., Vol. 279, Issue 4, 2499-2506, January 23, 2004

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Nitric Oxide Production and Regulation of Endothelial Nitric-oxide Synthase Phosphorylation by Prolonged Treatment with Troglitazone

EVIDENCE FOR INVOLVEMENT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) -DEPENDENT AND PPAR-INDEPENDENT SIGNALING PATHWAYS^*

Du-Hyong Cho, Yoon Jung Choi, Sangmee Ahn Jo, and Inho Jo

From the Department of Biomedical Sciences, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, Korea

Recently, peroxisome proliferator-activated receptor (PPAR) ligands have been reported to increase endothelial NO, but the signaling mechanisms involved are unknown. Using troglitazone, a PPAR ligand known as an antidiabetic compound, we investigated the molecular mechanism of its effect on NO production in bovine aortic endothelial cells. Troglitazone increased endothelial NO production in a dose- and time-dependent manner with no alteration in endothelial nitric-oxide synthase (eNOS) expression. The maximal increase (3.1-fold) was achieved with 20 µM troglitazone treatment for 12 h, and this increase was accompanied by increases in the expression of vascular endothelial growth factor (VEGF) and its receptor, KDR/Flk-1, and in Akt phosphorylation. Analysis with antibodies specific for each phosphorylated site demonstrated that troglitazone (20 µM treatment for 12 h) significantly increased both the phosphorylation of Ser¹¹⁷⁹ of eNOS (eNOS-Ser¹¹⁷⁹) and the dephosphorylation of eNOS-Ser¹¹⁶ but did not alter eNOS-Thr⁴⁹⁷ phosphorylation. Treatment with anti-VEGF antibody to scavenge the increased VEGF induced by troglitazone partially inhibited troglitazone-stimulated NO production. This was accompanied by the attenuation of troglitazone-stimulated increases in the phosphorylation of Akt and eNOS-Ser¹¹⁷⁹ with no alteration in eNOS-Ser¹¹⁶ dephosphorylation. We also found that bisphenol A diglycidyl ether, a PPAR antagonist, partially inhibited troglitazone-stimulated NO production with a concomitant reduction in VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser¹¹⁷⁹ phosphorylation but with no alteration in eNOS-Ser¹¹⁶ dephosphorylation induced by troglitazone. Taken together, our results demonstrate that prolonged treatment with troglitazone increases endothelial NO production by at least two independent signaling pathways: PPAR-dependent, VEGF-KDR/Flk-1-Akt-mediated eNOS-Ser¹¹⁷⁹ phosphorylation and PPAR-independent, eNOS-Ser¹¹⁶ dephosphorylation.

Received for publication, August 26, 2003 , and in revised form, October 10, 2003.

^* This work was supported in part by Korea National Institute of Health Intramural Research Grant 348-6111-213-000-207 (to I. J. and S. A. J.) and by a Biomedical Brain Research Center grant from the Ministry of Health and Welfare (to S. A. J.). 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.

To whom correspondence should be addressed: Dept. of Biomedical Sciences, National Institute of Health, 5 Nokbun-dong, Eunpyung-gu, Seoul 122-701, Korea. Tel.: 82-2-380-1521; Fax: 82-2-388-0924; E-mail: inhojo{at}nih.go.kr.

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