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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22:1305.)
© 2002 American Heart Association, Inc.

Vascular Biology

Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21^WAF1-Dependent Pathway

Masataka Sata; Akihiro Takahashi; Kimie Tanaka; Miwa Washida; Nobukazu Ishizaka; Junya Ako; Masao Yoshizumi; Yasuyoshi Ouchi; Takahiro Taniguchi; Yasunobu Hirata; Mitsuhiro Yokoyama; Ryozo Nagai; Kenneth Walsh

From the Department of Cardiovascular Medicine (M.S., K.T., M.W., N.I., Y.H., R.N.) and the Department of Geriatric Medicine (J.A., M.Y., Y.O.), University of Tokyo Graduate School of Medicine, Tokyo, Japan; the Division of Cardiovascular and Respiratory Medicine (A.T., T.T., M.Y.), Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; and the Division of Cardiovascular Research (M.S., A.T., K.W.), St. Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, Mass.

Correspondence to Dr Masataka Sata, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail msata-circ{at}umin.ac.jp

Objective— N-(3'4'-dimethoxycinnamoyl)-anthranilic acid (tranilast) is a drug that has been shown to reduce the incidence of restenosis after angioplasty in middle-scale clinical trials. Despite clinical interest in this drug, the pharmacological actions of tranilast remain relatively unexplored at a molecular level.

Methods and Results— We evaluated the effects of tranilast on vascular smooth muscle cell (VSMC) proliferation in wild-type mice and in mice lacking a cyclin-dependent kinase inhibitor, p21^WAF1 (p21). Tranilast potently inhibited the proliferation of VSMC cultures derived from wild-type mice, but VSMCs derived from p21-deficient (p21-/-) mice were unaffected by this treatment. In a mouse femoral artery model of vascular injury, tranilast administration to wild-type mice led to an upregulation of p21 expression and a decrease in the number of proliferating VSMCs, as determined by immunostaining for proliferating cell nuclear antigen. In contrast, tranilast had no effect on the number of proliferating cell nuclear antigen–positive cells in the injured arteries of p21-/- mice. Administration of tranilast significantly reduced the neointimal VSMC hyperplasia in wild-type mice at 4 weeks but had no effect on lesion formation in p21-/- mice.

Conclusions— Our findings provide genetic evidence that tranilast inhibits intimal hyperplasia via a p21-dependent pathway, an activity that may contribute to its efficacy in the prophylactic treatment of postangioplasty restenosis.

Key Words: pharmacology • genetically altered mice • smooth muscle cells • restenosis • proliferation

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