Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor gamma.
OBJECTIVE
Telmisartan, an angiotensin II type 1 receptor (AT1R) antagonist, was found to have a unique property: it is a partial agonist of peroxisome proliferator-activated receptor gamma (PPARgamma). Since previous studies have demonstrated that PPARgamma activators suppressed AT1R expression, we examined whether telmisartan affects AT1R expression in vascular smooth muscle cells.


METHODS
Vascular smooth muscle cells were derived from the thoracic aorta of Wistar-Kyoto rat. Northern and Western blotting analysis were used to examine AT1R mRNA and protein expression, respectively. The DEAE-dextran method was used for transfection, and the promoter activity of AT1R was examined by luciferase assay.


RESULTS
Telmisartan decreased the expression of AT1R at the mRNA and protein levels in a dose- and time-dependent manner. Decreased AT1R promoter activity with unchanged mRNA stability suggested that telmisartan suppressed AT1R gene expression at the transcriptional level. However, the expression of AT1R was not suppressed by other AT1R antagonists such as candesartan or olmesartan. Since the suppression of AT1R expression was prevented by pretreatment with GW9662, a PPARgamma antagonist, PPARgamma should have participated in the process. The deletion and mutation analysis of the AT1R gene promoter indicated that a GC box located in the proximal promoter region is responsible for the telmisartan-induced downregulation.


CONCLUSIONS
Our data provides a novel insight into an effect of telmisartan: telmisartan inhibits AT1R gene expression through PPARgamma activation. The dual inhibition of angiotensin II function by telmisartan - AT1R blockade and downregulation - would contribute to more complete inhibition of the renin-angiotensin system.
Imayama
Ikuyo
I
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan.
Ichiki
Toshihiro
T
Inanaga
Keita
K
Ohtsubo
Hideki
H
Fukuyama
Kae
K
Ono
Hiroki
H
Hashiguchi
Yasuko
Y
Sunagawa
Kenji
K
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011921:Rats, Inbred WKY; D044140:Receptor, Angiotensin, Type 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000077333:Telmisartan; D014158:Transcription, Genetic / Q000187:drug effects
C457499:2-chloro-5-nitrobenzanilide; D047228:Angiotensin II Type 1 Receptor Blockers; D000813:Anilides; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D000077333:Telmisartan