on June 20, 2002
Published online before print June 20, 2002, doi: 10.1161/01.ATV.0000026614.72957.E7
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Submitted on March 10, 2002
Accepted on June 5, 2002
Mouse Genetic Evidence That Tranilast Reduces Smooth Muscle Cell Hyperplasia via a p21waf1-Dependent Pathway
Masataka Sata *;
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.
* To whom correspondence should be addressed. 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, p21waf1 (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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