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. 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-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 mu mol/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.