Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes

Peroxisome proliferator-activated receptor (PPAR)-gamma ligands thiazolidin ediones (TZDs) have recently been reported to be anti-hypertensive and anti -atherosclerotic. We have previously shown that one of the TZDs troglitazon e significantly suppressed the transcription of both thromboxane receptor ( TXR) and angiotensin II type 1 receptor(AT1R) genes in vascular smooth musc le cells (VSMCs) by activating PPAR-gamma, In the present study, we compare d the effects of troglitazone and other TZDs on the transcription of these genes. TXR and AT1R mRNAs in rat VSMCs were determined by semi-quantitative RT-PCR, Luciferase chimeric constructs containing either the 989-bp rat TX R gene promoter or the 1,969-bp rat AT1R gene promoter were transiently tra nsfected into VSMCs, The cells were incubated with troglitazone, RS-1455 Ia derivative of troglitazone which does not contain the hindered phenol rese mbling alpha -tocopherol), pioglitazone, or rosiglitazone for 12 h before h arvesting. mRNA expression levels of TXR and AT1R were significantly decrea sed by troglitazone in contrast to rosiglitazone, TXR gene and AT1R gene tr anscription was significantly suppressed by troglitazone in a dose-dependen t manner, while RS-1455 was less potent. Pioglitazone and rosiglitazone wea kly suppressed the transcription of both genes in a manner almost similar t o F18-1455. We have shown that troglitazone suppresses transcription of bot h the TXR and AT1R genes more potently than other TZDs. The structure of tr oglitazone and RS-1455 is identical except the hindered phenol, which is re cently recognized to function as an antioxidant, Moreover, we have shown th at the potency for activating PPAR-gamma is almost identical between trogli tazone and RS-1455, We therefore speculate that the strong transcriptional suppression of the TXR and AT1R genes by troglitazone may be mediated in pa rt by its antioxidant effect.