Simvastatin inhibits rosiglitazone-induced endothelial cell migration and vascular permeability through suppression of Akt phosphorylation

Abstract

The peroxisome proliferator-activated receptor (PPAR) family of nuclear hormone receptors consists of three subtypes; , / and . PPAR- agonists, a class of insulin-sensitizing drugs, have been widely used in the treatment of type 2 diabetes including hyperglycemia. Although PPAR- activation displays beneficial effects on glucose homeostasis and lipid metabolism, rosiglitazone, a PPAR- agonist, has been reported to cause a significant increase in the risk of cardiovascular complications. In this study, we investigated the direct effects of rosiglitazone on endothelial cells (ECs) migration and vascular permeability and its action mechanisms. Rosiglitazone induced EC migration in a concentration-dependent manner. In addition, rosiglitazone treatment significantly increased endothelial cell permeability and VEGF expression, accompanied by decreased levels of junction proteins ZO-1 and JAM-A. However, rosiglitazone-induced EC migration and permeability were remarkably reduced in the presence of specific inhibitor against Akt or PKCβ. When ECs were transfected with Akt siRNA, rosiglitazone-induced EC migration was significantly decreased and junction protein levels were also restored to those of control.Furthermore, rosiglitazone induced vascular leakage of retina and aorta in mice models. However, intraperitoneal administration of Akt inhibitor blocked the rosiglitazone-induced vascular leakages. Simvastatin also inhibits rosiglitazone-induces endothelial cell migration and vascular permeability through suppression of Akt phosphorylation. In conclusion, our results provide that rosiglitazone might affect vascular permeability and leakage in the aorta through activating the Akt signaling pathway and that simvastatin may modulate rosiglitazone-induced vascular permeability through suppression of Akt phosphorylation.