Peroxisome proliferation-activated receptor-γ ligands ameliorate experimental autoimmune myocarditis

Background: Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands have been shown to ameliorate a variety of inflammatory conditions. The present study tested the hypothesis that PPAR-γ 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-γ ligands, 15-deoxy-Δ^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-γ expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of PPAR-γ 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-γ 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-γ 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-γ may play a role in the pathophysiology of EAM. PPAR-γ 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-γ ligands such as 15d-PGJ₂ and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.