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Published ahead of print on July 20, 2006, doi:10.1165/rcmb.2006-0034OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 6, December 2006, 722-729

A more recent version of this article appeared on December 1, 2006
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Submitted on January 26, 2006
Revised on July 19, 2006

Role of RhoA Inactivation in Reduced Cell Proliferation of Human Airway Smooth Muscle by Simvastatin

Naoya Takeda1, Masashi Kondo1, Satoru Ito1, Yasushi Ito1, Kaoru Shimokata1, and Hiroaki Kume1*

1 Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan

* To whom correspondence should be addressed. E-mail: hkume{at}med.nagoya-u.ac.jp.

Enhanced proliferation of smooth muscle cells contributes to airway remodeling of bronchial asthma. Recently, statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, have been shown to inhibit proliferation of both vascular and airway smooth muscle cells independently of lowering cholesterol. However, the mechanisms remain to be elucidated. The purpose of this study was to determine molecular processes by which statins inhibit proliferation of human bronchial smooth muscle cells. Simvastatin (0.1 - 1.0 µM) significantly inhibited cell proliferation and DNA synthesis induced by FBS in a concentration-dependent manner. The inhibitory effects of simvastatin were antagonized by mevalonate and geranylgeranylpyrophosphate, whereas the effects were not affected by squalene and farnesylpyrophosphate. The anti-proliferative effects of simvastatin were mimicked by GGTI-286, a geranylgeranyltransferase-I inhibitor, C3 exoenzyme, an inhibitor of Rho, and Y-27632, an inhibitor of Rho-kinase, a target protein of RhoA. Western blot analysis showed that the level of membrane localization of RhoA (active Rho) was markedly increased by FBS and that the increased active RhoA by FBS was reduced by simvastatin. Moreover, the inhibitory effect of simvastatin on FBS-induced RhoA activation was also antagonized by geranylgeranylpyrophosphate, not by farnesylpyrophosphate. Since these isoprenoids are required for prenylation of small G proteins RhoA and Ras, respectively, the present results demonstrate that an inhibition in airway smooth muscle cell proliferation by simvastatin is due to preventing geranylgeranylation of RhoA, not farnesylation of Ras. Therefore, statins may have therapeutic potential for prohibiting airway remodeling in bronchial asthma.




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