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(Circulation. 2006;113:2613-2622.)
© 2006 American Heart Association, Inc.

Transplantation

Pioglitazone Prevents Acute and Chronic Cardiac Allograft Rejection

Hisanori Kosuge, MD; Go Haraguchi, MD; Noritaka Koga, MD; Yasuhiro Maejima, MD; Jun-ichi Suzuki, MD; Mitsuaki Isobe, MD

From the Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Mitsuaki Isobe, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail isobemi.cvm{at}tmd.ac.jp

Received October 10, 2005; revision received February 17, 2006; accepted March 28, 2006.

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.

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