Background--Peroxisome proliferator-activated receptor- 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.

Methods and 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- 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-, 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 µmol/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.