Peroxisome proliferator-activated receptor-γ ligands ameliorate experimental autoimmune myocarditis associated with inhibition of self-sensitive T cells

Objective: Recent evidence has suggested that peroxisome proliferator-activated receptor-γ (PPAR-γ) serves as a negative regulator in the immune system. In the present study, we investigated the expression of PPAR-γ and the effect of PPAR-γ ligands on experimental autoimmune myocarditis (EAM). Methods and Results: Experimental autoimmune myocarditis was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-γ ligands 15-deoxy-Δ^12,14-PGJ ₂ 200 μg · kg^-1 · d^-1 by ip and pioglitazone 10 mg · kg^-1 · d^-1 by oral were administered for 3 weeks. PPAR-γ expression was upregulated in myocarditis and the enhanced PPAR-γ expression was prominently stained in the nuclear and perinuclear regions of the positive-stained cells in the inflammatory lesions. Administration of PPAR-γ ligands markedly reduced the severity of myocarditis, as indicated by the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores, and microscopic scores. The upregulated PPAR-γ expression was also reduced by PPAR-γ ligands treatment. In addition, PPAR-γ ligands suppressed the proliferative response and interferon-γ production of T cell-enriched splenocytes from rats with EAM. Furthermore, the cytotoxic activity and myocarditogenic potential of these T cells were inhibited by PPAR-γ ligands treatment. Conclusions: PPAR-γ ligands ameliorate EAM associated with inhibition of expansion and activation of the self-sensitive T cells. These results suggest that PPAR-γ ligands may have the potential to modulate human inflammatory heart diseases as myocarditis.