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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1896.)
© 2001 American Heart Association, Inc.

Vascular Biology

Downregulation of Angiotensin II Type 1 Receptor by Hydrophobic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors in Vascular Smooth Muscle Cells

Toshihiro Ichiki; Kotaro Takeda; Tomotake Tokunou; Naoko Iino; Kensuke Egashira; Hiroaki Shimokawa; Katsuya Hirano; Hideo Kanaide; Akira Takeshita

From the Departments of Cardiovascular Medicine (T.I., K.T., T.T., N.I., K.E., H.S., A.T.) and Molecular Cardiology (K.H., H.K.), Kyushu University Graduate School of Medical Sciences, 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

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, so-called statins, reduce the relative risk of a major coronary event by lowering the serum cholesterol level. In addition, statins may confer beneficial effects by cholesterol-lowering independent mechanisms, which are incompletely characterized. Because angiotensin II (Ang II) plays crucial roles in the pathogenesis of cardiovascular diseases, we examined the effect of statins on the expression of the Ang II type 1 receptor (AT₁-R) in cultured vascular smooth muscle cells (VSMCs). Cerivastatin and fluvastatin reduced the AT₁-R mRNA and the AT₁-R protein levels; however, pravastatin lacked this effect. Cerivastatin and fluvastatin suppressed the AT₁-R promoter activity measured by luciferase assay but did not affect AT₁-R mRNA stability, suggesting that the suppression occurs at the transcriptional level. Coincubation of VSMCs with mevalonate or geranylgeranyl pyrophosphate but not with farnesyl pyrophosphate reversed the cerivastatin-induced AT₁-R downregulation. Overexpression of dominant-negative Rho A also suppressed AT₁-R mRNA expression. Treatment with cerivastatin for 24 hours reduced the calcium response of VSMCs to Ang II. Taken together, statins downregulate AT₁-R expression through a mevalonate-dependent, geranylgeranyl pyrophosphate-dependent, and Rho A-dependent manner and attenuate the biological function of Ang II. Downregulation of AT₁-R may contribute to the cholesterol-independent beneficial effect of statins on the cardiovascular system.

Key Words: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors • angiotensin II receptors • vascular smooth muscle cells • mevalonate • geranylgeranylation

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