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(Hypertension. 2000;35:297.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Downregulation of Angiotensin II Type 1 Receptor by All-trans Retinoic Acid in Vascular Smooth Muscle Cells

Kotaro Takeda; Toshihiro Ichiki; Yuko Funakoshi; Kiyoko Ito; Akira Takeshita

From the Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Higashi-ku, Fukuoka, Japan.

Correspondence to Toshihiro Ichiki, MD, Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan. E-mail ichiki{at}cardiol.med.kyushu-u.ac.jp

Abstract—All-trans retinoic acid (atRA) is a biologically active metabolite of vitamin A that plays an important role in cell differentiation and proliferation. Although neointimal formation after balloon injury of rat carotid artery is inhibited by atRA, the mechanisms are not clearly understood. Because the renin-angiotensin system is one of the crucial components of atherosclerosis, we examined the effects of atRA on the expression of angiotensin II type 1 receptor (AT₁-R) in vascular smooth muscle cells. atRA (1 µmol/L) decreased the AT₁-R mRNA level by 50% after 24 hours; AT₁-R number was also reduced to the same extent after 48 hours. atRA markedly suppressed promoter activity of the AT₁-R promoter-luciferase construct, but AT₁-R mRNA stability was not affected. Cycloheximide blocked the atRA-induced decrease in AT₁-R mRNA expression, suggesting that this process requires de novo protein synthesis. Simultaneous treatment with an agonist (Ro40-6055) specific for retinoic acid receptor (RAR) and an agonist (Ro25-7836) specific for retinoid X receptor (RXR) suppressed the AT₁-R mRNA expression comparable to that with treatment with atRA, suggesting that the RAR/RXR heterodimer mediates the effect of atRA in AT₁-R downregulation. These results suggest that atRA suppressed AT₁-R mRNA transcription through new protein synthesis induced by RAR/RXR-dependent transcription. This study provides novel insight into a role of atRA as an important molecule that regulates AT₁-R gene expression and provides possible mechanisms for the suppression of neointimal formation by atRA.

Key Words: receptors, angiotensin II • muscle, smooth, vascular • genes • all-trans retinoic acid

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