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

Recent evidence shows that peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ ligand in human umbilical vein endothelial cells. We found that the antiangiogenic effects of rosiglitazone were reversed by either bisphenol A diaglycidyl ether, a PPARγ 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 PPARγ activation, suggesting that rosiglitazone activates maxi-K channel via PPARγ. In the rosiglitazone-induced antiangiogenic process, endothelial nitric-oxide synthase-Ser1179 phosphorylation and NO production were significantly elevated, and treatment with the NOS inhibitor NG-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 PPARγ-mediated NO production, followed by maxi-K channel opening.

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