Abstract 358: Telmisartan Downregulates Angiotensin II Type-1 Receptor through Peroxisome Proliferator Activated Receptor Gamma
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor which plays an important role in lipid and glucose metabolism. It is also known that PPARγ has anti-inflammatory effects which work negatively on atherogenesis. Our previous results have shown that activators of PPARγ such as 15 deoxy-Δ12,14-prostaglandin J2 and pioglitazone (Pio) decreased expression of Angionsin II type-1 receptor (AT1R) in vascular smooth muscle cells (VSMCs). Telmisartan (Tel), an unique angiotensin II receptor blocker (ARB) generally used as an anti-hypertensive drug, has recently been reported to promote adipocyte maturation through activation of PPARγ. We examined whether Tel, a partial agonist of PPARγ, affects the expression of Angiotensin II type 1 receptor (AT1R) in a similar way to PPARγ agonists in VSMCs. Tel (10γmol/L) decreased AT1R expression in both mRNA and protein level after 12 hours of stimulation. This suppression was blocked by pretreating VSMCs with GW9662, a PPARγ antagonist, suggesting that they are mediated by PPARγ. The AT1R promoter activity measured by luciferase assay was significantly reduced after 12 hours of Tel administration. However AT1R mRNA stability was not changed. Further examination with deletion mutants and the Sp1 binding site-mutated AT1R promoter luciferase construct revealed that the Sp1 binding site within the AT1R promoter region was essential for the Tel induced AT1R suppression. We also examined effects of other ARBs, olmesartan and candesartan, on AT1R expression and found that suppression of AT1R was unique to Tel. The same results were obtained in animal study using Wistar-Kyoto rats. Tel treatment suppressed the expression of AT1R in thoracic aorta. However, AT1R suppression was not observed by olmesartan or candesartan. These results suggest that Tel suppresses AT1R mRNA expression at the transcriptional level without changing its stability. Our result provides a novel insight into an effect of Tel, not only blocking AT1R but also regulating AT1R gene expression. These dual effects of Tel on AT1R blockade and AT1R down-regulation should be beneficial for the treatment of cardiovascular diseases through more complete inhibition of the renin-angiotensin system.