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J. Biol. Chem., Vol. 281, Issue 19, 13503-13512, May 12, 2006

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Antiangiogenic Effect of Rosiglitazone Is Mediated via Peroxisome Proliferator-activated Receptor -activated Maxi-K Channel Opening in Human Umbilical Vein Endothelial Cells^*

From the Medicinal Science Division, Korea Research Institute of Chemical Technology, P. O. Box 107, Yuseong-gu, Daejeon 305-600, Korea

Recent evidence shows that peroxisome proliferator-activated receptor (PPAR) ligands induce the antiangiogenic effect in endothelial cells and tumors. In the present study, we elucidated the involvement of maxi-K channel activation in the antiangiogenic effect of rosiglitazone, a well known PPAR ligand in human umbilical vein endothelial cells. We found that the antiangiogenic effects of rosiglitazone were reversed by either bisphenol A diaglycidyl ether, a PPAR antagonist, or iberiotoxin, a maxi-K channel blocker. Knockdown of maxi-K channel expression also reversed the antiangiogenic effects. Iberiotoxin reversed the rosiglitazone-induced hyperpolarization while having no effect on the endogenous PPAR activation, suggesting that rosiglitazone activates maxi-K channel via PPAR. In the rosiglitazone-induced antiangiogenic process, endothelial nitric-oxide synthase-Ser¹¹⁷⁹ phosphorylation and NO production were significantly elevated, and treatment with the NOS inhibitor N^G-monomethyl-L-arginine acetate abolished the antiangiogenic and apoptotic effects of rosiglitazone, indicating NO as a key mediator of the rosiglitazone actions. In conclusion, rosiglitazone significantly inhibited VEGF₁₆₅-induced angiogenesis by a proapoptotic mechanism via PPAR-mediated NO production, followed by maxi-K channel opening.

Received for publication, September 21, 2005 , and in revised form, January 10, 2006.

^* This research was supported by a grant from the Center for Biological Modulators of the 21st Century Frontier R&D Program, the Ministry of Science and Technology, Korea. 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. Tel.: 82-42-860-7542; Fax: 82-42-861-0770; E-mail: hgcheon{at}krict.re.kr.

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