Pioglitazone prevents acute and chronic cardiac allograft rejection.
BACKGROUND
Peroxisome proliferator-activated receptor-gamma plays an important role in regulating inflammation. Although cardiac transplantation is an established therapy for patients with end-stage heart disease, allograft rejection is a major concern for long-term survival. We investigated the role of pioglitazone in acute and chronic rejection in a murine cardiac transplantation model.


RESULTS
We performed heterotopic murine cardiac transplantation in total allomismatch or major histocompatibility complex class II-mismatched combinations. Recipient mice were given standard chow or chow containing pioglitazone (3 mg.kg(-1).d(-1)) beginning 1 day before cardiac transplantation. In acute rejection, animals given pioglitazone showed significantly longer cardiac allograft survival than control mice (mean survival time, 34.6+/-7.8 versus 8.4+/-0.4 days; P<0.003). Treatment with pioglitazone significantly suppressed graft expression of interferon-gamma and monocyte chemoattractant protein-1. In chronic rejection, neointimal hyperplasia was significantly lower in allografts from mice treated with pioglitazone (luminal occlusion, 25.1+/-8.8%) than in those from control mice (65.8+/-7.3%, P<0.001). Pioglitazone-treated allografts showed significantly reduced expression of interferon-gamma, interleukin-10, and monocyte chemoattractant protein-1. We performed mixed lymphocyte reactions and in vitro proliferation assays of smooth muscle cells. Addition of pioglitazone to mixed lymphocyte reactions inhibited proliferation of T cells. Smooth muscle cells showed significant proliferation when cocultured with activated splenocytes. This proliferation was significantly inhibited by the addition of pioglitazone (1 micromol/L).


CONCLUSIONS
Pioglitazone prolongs allograft survival and attenuates neointimal hyperplasia through the suppression of proliferation of smooth muscle cells. Pioglitazone may be a novel means to prevent acute and chronic allograft rejection.
Kosuge
Hisanori
H
Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Haraguchi
Go
G
Koga
Noritaka
N
Maejima
Yasuhiro
Y
Suzuki
Jun-ichi
J
Isobe
Mitsuaki
M
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000473:pathology / Q000502:physiology*; D006965:Hyperplasia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics / Q000502:physiology; D016753:Interleukin-10 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology; D000077205:Pioglitazone; D013601:T-Lymphocytes / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D014184:Transplantation, Homologous
D018932:Chemokine CCL2; D047495:PPAR gamma; D045162:Thiazolidinediones; D016753:Interleukin-10; D007371:Interferon-gamma; D000077205:Pioglitazone