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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1506.)
© 2005 American Heart Association, Inc.

Thrombosis

Rac1 Regulation of Surface Expression of Protease-Activated Receptor-1 and Responsiveness to Thrombin in Vascular Smooth Muscle Cells

Tatsuya Yufu; Katsuya Hirano; Dan Bi; Mayumi Hirano; Junji Nishimura; Yukihide Iwamoto; Hideo Kanaide

From the Division of Molecular Cardiology (T.Y., K.H., D.B., M.H., J.N., H.K.), Research Institute of Angiocardiology, the Department of Orthopedics (Y.I.), Graduate School of Medical Sciences, and the Kyushu University COE Program on Lifestyle-Related Diseases (H.K.), Kyushu University, Fukuoka, Japan.

Correspondence to Hideo Kanaide, MD, PhD, Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582. E-mail kanaide{at}molcar.med.kyushu-u.ac.jp

Objective— Protease-activated receptor-1 (PAR1) mediates the thrombin-induced proliferation and hypertrophy of vascular smooth muscle cells. A role of Rac1 in the regulation of PAR1 expression was investigated.

Methods and Results— Treatment with simvastatin, a hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, for 24 hours attenuated the transient [Ca²⁺]_i elevation induced by thrombin. Immunofluorescence staining revealed that simvastatin decreased the surface expression of PAR1 in a manner dependent on protein geranylgeranylation. Introduction of a Rac1/Cdc42 inhibitory fragment but not a RhoA inhibitory fragment using a cell-penetrating peptide also attenuated the response to thrombin and decreased the surface expression of PAR1. Finally, downregulation of Rac1, but not RhoA, using an RNA interference technique attenuated the thrombin-induced [Ca²⁺]_i elevation. However, the level of PAR1 mRNA and the total amount of PAR1 protein remained unchanged.

Conclusions— Here, we provide for the first time 3 lines of evidence that Rac1 plays a critical role in maintaining the surface expression of PAR1 and the responsiveness to thrombin in vascular smooth muscle cells. Rac1 is suggested to regulate the constitutive trafficking of PAR1 and thereby regulate the surface expression of PAR1.

We provided evidence that Rac1 regulates the surface expression of thrombin receptor PAR1 in vascular smooth muscle. Inhibition of Rac1 by hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor, a Rac1/Cdc42 inhibitory fragment, and an RNA interference technique reduced the surface expression of PAR1 and the responsiveness to thrombin.

Key Words: expression • protease-activated receptor • Rac1 • smooth muscle • thrombin

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