Rosiglitazone suppresses cyclosporin-induced chronic transplant dysfunction and prolongs survival of rat cardiac allografts.
BACKGROUND
The lack of effective treatment for chronic transplant dysfunction restricts the long-term survival of solid organ allografts. Peroxisome proliferator-activated receptor ligands can suppress vascular inflammation. The aim of this study was to analyze the effects of rosiglitazone on chronic transplant dysfunction in a rat cardiac transplant model.


METHODS
Inbred male Fisher 344 (F344, RT1lvl) and Lewis (LEW, RT1(1)) rats were subjected to heterotopic abdominal heart transplantation according to standard procedures. Cyclosporine A was administered intraperitoneally to cover acute rejection, and rosiglitazone was administered orally by gavage daily from 3 days before the operation to the end of experiments.


RESULTS
Rosiglitazone significantly prolonged the survival of cardiac allografts in rats (F344 to LEW) that had received a 10-day course of cyclosporin A compared to treatment with immunosuppressant alone. Analysis of allografts at 120 days posttransplantation showed that rosiglitazone reduced the inflammatory cell infiltrate in both the vessels and graft parenchyma as were neointimal formation, vascular occlusion, and fibrosis. Expression of transforming growth factor-beta and related proteins was less abundant after cyclosporin A/rosiglitazone treatment.


CONCLUSIONS
The findings reported here demonstrate that rosiglitazone given under the cover of short-term treatment with cyclosporin A prolongs cardiac allograft survival and reduces the severity of chronic transplant dysfunction. This may be mediated in part through the downregulation of transforming growth factor-beta and related proteins. The combined effects of rosiglitazone and immunosuppressive drugs are potentially beneficial to patients receiving organ transplants.
Chen
Yan
Y
Department of Surgery, Faculty of Medicine Building, University of Hong Kong, Pokfulam, Hong Kong, SAR China.
Liu
Yan
Y
Yuan
Zhengwei
Z
Tian
Lina
L
Dallman
Margaret J
MJ
Thompson
Paul W
PW
Tam
Paul K H
PK
Lamb
Jonathan R
JR
D000818:Animals; D016572:Cyclosporine / Q000009:adverse effects*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000009:adverse effects; D008297:Male; D023421:Models, Animal; D016133:Polymerase Chain Reaction; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D014184:Transplantation, Homologous; D014665:Vasodilator Agents / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D018125:Receptors, Transforming Growth Factor beta; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D016572:Cyclosporine