Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes.
Peroxisome proliferator-activated receptor (PPAR)-gamma ligands thiazolidinediones (TZDs) have recently been reported to be anti-hypertensive and anti-atherosclerotic. We have previously shown that one of the TZDs troglitazone significantly suppressed the transcription of both thromboxane receptor (TXR) and angiotensin II type 1 receptor (AT1R) genes in vascular smooth muscle cells (VSMCs) by activating PPAR-gamma. In the present study, we compared 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 TXR gene promoter or the 1,969-bp rat AT1R gene promoter were transiently transfected into VSMCs. The cells were incubated with troglitazone, RS-1455 (a derivative of troglitazone which does not contain the hindered phenol resembling alpha-tocopherol), pioglitazone, or rosiglitazone for 12 h before harvesting. mRNA expression levels of TXR and AT1R were significantly decreased by troglitazone in contrast to rosiglitazone. TXR gene and AT1R gene transcription was significantly suppressed by troglitazone in a dose-dependent manner, while RS-1455 was less potent. Pioglitazone and rosiglitazone weakly suppressed the transcription of both genes in a manner almost similar to RS-1455. We have shown that troglitazone suppresses transcription of both the TXR and AT1R genes more potently than other TZDs. The structure of troglitazone and RS-1455 is identical except the hindered phenol, which is recently recognized to function as an antioxidant. Moreover, we have shown that the potency for activating PPAR-gamma is almost identical between troglitazone and RS-1455. We therefore speculate that the strong transcriptional suppression of the TXR and AT1R genes by troglitazone may be mediated in part by its antioxidant effect.
Sugawara
A
A
Department of Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan. akiras2i@mail.cc.tohoku.ac.jp
Takeuchi
K
K
Uruno
A
A
Ikeda
Y
Y
Arima
S
S
Sato
K
K
Kudo
M
M
Taniyama
Y
Y
Ito
S
S
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000235:genetics*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D000077288:Troglitazone; D024502:alpha-Tocopherol / Q000737:chemistry
D002839:Chromans; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D018160:Receptors, Cytoplasmic and Nuclear; D017482:Receptors, Thromboxane; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; D024502:alpha-Tocopherol; D000077288:Troglitazone; D000077205:Pioglitazone