Telmisartan Blocks Advanced Glycation End Product (AGE)-Induced Plasminogen Activator Inhibitor-1 (PAI-1) Gene Expression in Endothelial Cells via Activation of Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ )

Abstract

Advanced glycation end product (AGE) and receptor (RAGE) axis play a central role in the pathogenesis of diabetic vascular complications. Since peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been reported to reduce RAGE gene expression and subsequently suppress the downstream signalings in human umbilical vein endothelial cells (HUVECs), we examined here whether telmisartan, a unique angiotensin II type 1 receptor blocker with PPAR-γ agonistic activity, could inhibit the AGE-induced up-regulation of plasminogen activator inhibitor-1 (PAI-1) mRNA levels in HUVECs by suppressing RAGE gene expression. Telmisartan completely blocked the AGE-induced RAGE gene up-regulation in HUVECs, which was partly prevented by GW9662, an inhibitor of PPAR-γ. Further, telmisartan was also found to inhibit up-regulation of mRNA levels for PAI-1 in AGE-exposed HUVECs, which was completely prevented by GW9662. These results suggest that telmisartan inhibits the AGE-induced PAI-1 gene induction in HUVECs by down-regulating RAGE expression via PPAR-γ activation. Our present study suggests that telmisartan works as an anti-thrombogenic agent against AGEs, which may play a protective role against vascular complications in diabetes.