Tranilast inhibits cardiac allograft vasculopathy in association with p21(Waf1/Cip1) expression on neointimal cells in murine cardiac transplantation model.
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.
Izawa
A
A
First Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Suzuki Ji
Takahashi
W
W
Amano
J
J
Isobe
M
M
D000818:Animals; D017209:Apoptosis; D001835:Body Weight; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000276:immunology / Q000378:metabolism*; D006085:Graft Survival; D016027:Heart Transplantation / Q000009:adverse effects*; D007150:Immunohistochemistry; D007700:Kinetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000276:immunology; D014184:Transplantation, Homologous; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000276:immunology; D062367:ortho-Aminobenzoates / Q000494:pharmacology* / Q000627:therapeutic use
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D018809:Proliferating Cell Nuclear Antigen; D016159:Tumor Suppressor Protein p53; D062367:ortho-Aminobenzoates; C012293:tranilast