血管紧张素受体1阻断剂替米沙坦、厄贝沙坦具有激活PPARα的作用

Angiotensin type 1 receptor blockers telmisartan and irbesartan activate PPARα

目的通过观察替米沙坦、厄贝沙坦对PPARα转录活性的影响以探讨其改善糖脂代谢的机制。方法将构建的PPARα表达质粒、PPAR反应元件（PPRE）调控的荧光素酶表达质粒与pRL表达载体以脂质体（SuperFect）瞬时共转染COS-7细胞后，分别加入不同浓度的替米沙坦及厄贝沙坦，继续培养细胞不同时间，用双荧光素酶基因报告系统检测荧光素酶活性以反映PPARα转录活性。不同浓度的厄贝沙坦及替米沙坦孵育3T3-L1脂肪细胞，分别应用RT—PCR和Western印迹测定细胞的PPARα mRNA和蛋白表达水平。结果（1）替米沙坦和厄贝沙坦均呈剂量和时间依赖性地增加COS-7细胞的PPARα转录活性，在60h作用均达高峰，两者在100μmol／L浓度时PPRE调控的荧光素酶活性较对照组增高3．8倍和2．6倍（均P〈0．01）；（2）替米沙坦及厄贝沙坦激活PPARα的作用不能被PPARγ特异性抑制剂GW9662抑制；（3）替米沙坦和厄贝沙坦呈剂量依赖性增加3T3-L1脂肪细胞PPARα mRNA和蛋白表达水平。结论血管紧张素受体阻断剂替米沙坦和厄贝沙坦增加PPARα转录活性，可能通过此途径改善糖脂代谢。

Objective To investigate the effect of telmisartan and irbesartan on PPARα transcriptional activity, and to clarify their molecular mechanisms in improving glucose and lipid metabolism. Methods The structural expression vectors, including pCMV-PPARα, pGL3-PPRE and the internal control vector pRL-TK, were transiently co-transfected into COS-7 cells using SuperFeet, the cells were continously cultured with various concentrations of telmisartan and irbesartan, and then the PPRE controlled luciferase activity was determined by using a dual-luciferase reporter gene assay system. PPARα mRNA and protein expression levels were detected by RT-PCR and Western blot after 3T3-L1 adipocytes were treated with various concentrations of telmisartan or irbesartan. Results （1） Both telmisartan and irbesartau stimulated PPARα transcriptional activity in concentration-and time-dependent manners in cultured COS-7 cells with the maximal effect at 60 h, with the results increased by 3.8 and 2.6 folds respectively at the concentration of 100 μ mol/L compared with control group （both P〈0.01）. （2） The PPARγ antagonist GW9662 did not inhibit fenofibrate, telmisartan and irbesartan-stimulated PPARα transcriptional activities. （3） Both telmisartan and irbesartan increased PPARα mRNA and protein expression levels in a dose-dependent manner in 3T3-L1 adipoeytes. Conclusion Angiotensin type 1 receptor blockers, telmisartan and irbesartan, can both increase PPARα transcriptional activity, which may contribute to their metabolic effects.