Abstract 2967: Peroxisome Proliferation-Activated Receptor-Gamma Ligands Ameliorate Experimental Autoimmune Myocarditis
Peroxisome proliferator-activated receptor-γ (PPAR-γ) ligands have been shown to ameliorate a variety of inflammatory conditions by modulating inflammatory processes. We tested the hypothesis that PPAR-γ ligands reduce experimental autoimmune myocarditis (EAM) associated with inhibition of activation of T cells and of proinflammatory cytokines.
<Methods > EAM was induced in Lewis rats by immunization with porcine cardiac myosin. PPAR-γ ligands, 15-deoxy-Δ-prostaglandin2 (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 (each n = 7–9). 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 and microscopic scores compared with untreated controls. PPAR-γ ligands suppressed not only myocardial mRNA expression of inflammatory cytokines but the expression of interleukin (IL)-β 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 against cultured myocytes and myocardiogenic potential of these T cells were inhibited by 15d-PGJ2 treatment. PPAR-γ ligands ameliorated EAM associated with suppression of the expansion of myocardiogenic T cells and the activation of cytotoxic 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, where activated T cells and inflammatory cytokines play an important role in the disease development.