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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1172.)
© 2001 American Heart Association, Inc.

Vascular Biology

Tranilast Inhibits Cardiac Allograft Vasculopathy in Association With p21^Waf1/Cip1 Expression on Neointimal Cells in Murine Cardiac Transplantation Model

Atsushi Izawa; Jun-ichi Suzuki; Wataru Takahashi; Jun Amano; Mitsuaki Isobe

From the First Department of Internal Medicine (A.I., J.S., W.T.) and the Second Department of Surgery (J.A.), Shinshu University School of Medicine, Matsumoto, and the Department of Cardiovascular Medicine (M.I.), Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Mitsuaki Isobe, MD, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail isobemi.med3{at}tmd.ac.jp

Abstract—Cardiac allograft vasculopathy is a major complication after cardiac transplantation, often limiting long-term recipient survival. N-(3,4-Dimethoxycinnamoyl)anthranilic acid (tranilast) inhibits cyclin-dependent kinase activity through p21^Waf1/Cip1 induction and arrests vascular smooth muscle cell proliferation in vitro. We tested a hypothesis that tranilast inhibits the vasculopathy characterized by diffuse intimal thickening in a murine heart transplantation model. Hearts from DBA/2 mice were heterotopically transplanted into B10.D2 mice as allografts. Oral administration of tranilast started 3 days before transplantation at doses of 550 or 1040 mg/kg per day until the animals were killed. Cardiac allograft vasculopathy was defined as luminal stenosis caused by neointimal formation. The percentage of luminal stenosis and cardiac rejection were analyzed 14 and 28 days after transplantation. Tranilast administration was associated with a marked reduction in luminal occlusion but with no significant effect on cardiac rejection. Immunohistochemical study of the tranilast-treated graft coronary arteries revealed enhancement of p21^Waf1/Cip1 and decreased expression of proliferating cell nuclear antigen in the neointima. The significant reduction in allograft vasculopathy concomitant with the enhancement of p21^Waf1/Cip1 indicates that tranilast has an antiproliferative effect that could be applicable to clinical treatment of cardiac allograft vasculopathy.

Key Words: transplantation • cardiac allograft vasculopathy • prevention • proliferating cell nuclear antigen • p21^Waf1/Cip1

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