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Cardiovascular Research 2003 59(3):685-694; doi:10.1016/S0008-6363(03)00457-7
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Peroxisome proliferation-activated receptor-{gamma} ligands ameliorate experimental autoimmune myocarditis

Zuyi Yuana,*, Yan Liua, Yu Liua, Jijun Zhanga, Chiharu Kishimotob, Yanni Wanga, Aiqun Maa and Zhiquan Liua

aDepartment of Cardiovascular Medicine, First Hospital of Xi’an Jiaotong University, No. 1 Jiankang Road, Xi’an, Shaanxi 710061, China
bDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan

zuyiyuan{at}mail.xjtu.edu.cn

* Corresponding author. Tel.: +86-29-532-4021; fax: +86-29-526-3190.

Background: Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) ligands have been shown to ameliorate a variety of inflammatory conditions. The present study tested the hypothesis that PPAR-{gamma} ligands reduce experimental autoimmune myocarditis (EAM) associated with inhibition of the expansion and activation of T cells, as well as suppression of the expression of proinflammatory cytokines. Methods and results: EAM was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-{gamma} ligands, 15-deoxy-{Delta}12,14-PGJ2 (15d-PGJ2) 200 µg/kg/day i.p. and pioglitazone (PIO) 10 mg/kg/day orally, were administered for 3 weeks to rats with EAM. The results showed that enhanced PPAR-{gamma} expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of PPAR-{gamma} ligands markedly reduced the severity of myocarditis, as shown by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. PPAR-{gamma} ligands suppressed myocardial mRNA expression of inflammatory cytokines and the expression of interleukin (IL)-1β protein in rats with EAM. In addition, 15d-PGJ2 and PIO treatment suppressed the proliferative response and interferon-{gamma} production of T cell-enriched splenocytes from rats with EAM. Furthermore, the cytotoxic activity and myocardiogenic potential of these T cells were inhibited by 15d-PGJ2 treatment. Conclusions: PPAR-{gamma} may play a role in the pathophysiology of EAM. PPAR-{gamma} ligands ameliorate the EAM associated with suppression of the expansion and activation of myocardiogenic T cells, as well as inhibition of the expression of proinflammatory cytokines. These results suggest that PPAR-{gamma} ligands such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.

KEYWORDS Myocarditis; Immunity; T cells; PPAR-{gamma}; Cytokines


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