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Papers In Press, published online ahead of print October 30, 2003
Department of Biomedical Sciences, National Institute of Health, Seoul, Seoul 122-701
Corresponding Author: inhojo{at}nih.go.kr
Recently, peroxisome proliferator-activated receptor
J. Biol. Chem, 10.1074/jbc.M309451200
Submitted on August 26, 2003
Revised on October 10, 2003
Accepted on October 30, 2003
Nitric oxide production and regulation of endothelial nitric oxide synthase phosphorylation by prolonged treatment with troglitazone: Evidence for involvement of PPARgamma-dependent and PPARgamma-independent signaling pathways
(PPAR) ligands have been reported to increase endothelial nitric oxide (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 NO synthase (eNOS) expression. The maximal increase (approximately 3.1-fold) was achieved with 20 
M troglitazone treatment for 12 h, and this increase was accompanied by increases in the expression of VEGF and its receptor, KDR/Flk-1, and in Akt phosphorylation. Analysis with antibodies specific for each phosphorylated site demonstrated that troglitazone (20 M 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 (BADGE), 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.
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