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

Abstract

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-Ser 1179 phosphorylation and NO production were significantly elevated, and treatment with the NOS inhibitor N Gmonomethyl-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 VEGF 165 -induced angiogenesis by a proapoptotic mechanism via PPAR␥-mediated NO production, followed by maxi-K channel opening.

Peroxisome Proliferator-Activated Receptor-γ–Mediated Effects in the Vasculature

“…50 -52 The mechanisms involve the suppression of VEGF receptors and urokinase plasminogen activator expression, induction of PAI-1, and elevation of apoptosis and NO production. 50,52 All these data have clearly demonstrated the importance of PPAR-␥ in regulating endothelial biology (Figure 1). …”

Rosiglitazone Stimulates Nitric Oxide Synthesis in Human Aortic Endothelial Cells via AMP-activated Protein Kinase*

“…Recent studies have suggested that prolonged exposure to thiazolidinediones directly improves NO bioavailability in endothelial cells and increases phosphorylation of eNOS at Ser-1177 (12)(13)(14)(15). Phosphorylation of eNOS at Ser-1177 stimulates NO synthesis, and several protein kinases have been demonstrated to phosphorylate eNOS Ser-1177 in endothelial cells, including protein kinase B (also known as Akt) and AMP-activated protein kinase (AMPK) (16 -20), but the protein kinase and signaling mechanism responsible for phosphorylation of eNOS in response to thiazolidinediones is as yet undetermined.…”

Reduction of large‐conductance Ca2+‐activated K+ channel with compensatory increase of nitric oxide in insulin resistant rats

“…NO can directly activate BK Ca [22] and can also be dependent on the nitric oxide-cyclic guanosine monophosphate-dependent protein kinase signal amplification system [23]. The regulation of endothelial BK Ca channel by NO is less clear [24].…”