Tranilast inhibits cardiac allograft vasculopathy in association with p21(Waf1/Cip1) expression on neointimal cells in murine cardiac transplantationmodel

Citation
A. Izawa et al., Tranilast inhibits cardiac allograft vasculopathy in association with p21(Waf1/Cip1) expression on neointimal cells in murine cardiac transplantationmodel, ART THROM V, 21(7), 2001, pp. 1172-1178
Citations number
44
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
ISSN journal
1079-5642 → ACNP
Volume
21
Issue
7
Year of publication
2001
Pages
1172 - 1178
Database
ISI
SICI code
1079-5642(200107)21:7<1172:TICAVI>2.0.ZU;2-G
Abstract
Cardiac allograft vasculopathy is a major complication after cardiac transp lantation, often limiting long-term recipient survival. N-(3,4-Dimethoxycin namoyl)anthranilic acid (tranilast) inhibits cyclin-dependent kinase activi ty 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 transpl anted into B10.D2 mice as allo,grafts. Oral administration of tranilast sta rted 3 days before transplantation at doses of 550 or 1040 mg/kg per day un til 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 transplan tation. Tranilast administration was associated with a marked reduction in luminal occlusion but with no significant effect on cardiac rejection. Immu nohistochemical study of the tranilast-treated graft coronary arteries reve aled enhancement of p21(Waf1/Cip1) and decreased expression of proliferatin g cell nuclear antigen in the neointima. The significant reduction in allog raft vasculopathy concomitant with the enhancement of p21(Waf1/Cip1) indica tes that tranilast has an antiproliferative effect that could be applicable to clinical treatment of cardiac allograft vasculopathy.