© 1999 American Heart Association, Inc.
Original Contribution |
Tranilast Inhibits Vascular Smooth Muscle Cell Growth and Intimal Hyperplasia by Induction of p21waf1/cip1/sdi1 and p53
From the First Department of Internal Medicine (A.T., T.T., M.Y.), Kobe University School of Medicine, Chuo-ku, Kobe, and the Faculty of Health Science (Y.I.), Suma-ku, Kobe, Japan.
Correspondence to Takahiro Taniguchi, MD, PhD, First Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-ku, Kobe 650-0017, Japan. E-mail taniguch{at}med.kobe-u.ac.jp
Abstract—Tranilast, which is an antiallergic drug, has a potent effect on preventing postangioplasty restenosis. To elucidate this mechanism, we studied the effect of tranilast on the proliferation of vascular smooth muscle cells (SMCs) in vitro and in vivo. Tranilast decreased the growth rate of SMCs stimulated by either 10% FBS or platelet-derived growth factor. The IC50 value, evaluated as cell number, was 100 µmol/L. These inhibitory effects were associated with inhibition of the retinoblastoma gene product (pRb) phosphorylation. Because pRb phosphorylation is regulated by cyclin-dependent kinases (CDK), we investigated CDK2 and CDK4 activities and the expression of CDK inhibitor p21waf1/cip1/sdi1 (p21). When SMCs were stimulated by 10% FBS or platelet-derived growth factor, CDK2 and CDK4 activities reached a maximum near the G1/S transition. Tranilast suppressed their activities by >80% without reduction of CDK2/cyclin E and CDK4/cyclin D1 protein levels. These inhibitory effects were associated with enhanced expression of p21 and elevated complexing of p21 with CDK2/CDK4. Next, rat balloon-injured carotid artery was analyzed for intimal thickening and p21 expression. Tranilast-treated rats had a 70% (P<0.001) smaller neointima/media area ratio at 14 days after balloon injury compared with the controls. Immunohistochemical staining demonstrated that, in tranilast-treated rats, p21 was already present in the neointima at day 7 and strongly expressed throughout the neointima at day 14. In control rats, p21 was not observed in the neointima at day 7 but was sparsely expressed at day 14. These data demonstrate that inhibition of CDK2/CDK4 activities by the increased expression of p21 may be one mechanism by which tranilast inhibits SMC proliferation and prevents postangioplasty restenosis.
Key Words: angioplasty • restenosis • signal transduction • carotid arteries • smooth muscle
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