Cardioprotective effects of peroxisome proliferator activated receptor γ activators on acute myocarditis:: anti-inflammatory actions associated with nuclear factor κB blockade

Objective: To test the hypothesis that activation of peroxisome proliferator activated receptor gamma (PPAR-gamma) reduces experimental autoimmune myocarditis (EAM) associated with inhibitor kappa B (I kappa B) alpha induction, blockade of nuclear factor kappa B (NF-kappa B), and inhibition of inflammatory cytokine expression. Methods: EAM was induced in Lewis rats by immunisation with porcine cardiac myosin. PPAR-gamma activators 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d- PGJ(2)) and pioglitazone (PIO) were administered to rats with EAM. Results: Enhanced PPAR-gamma expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of 15d- PGJ(2) and PIO greatly reduced the severity of myocarditis and suppressed myocardial mRNA and protein expression of inflammatory cytokines in rats with EAM. In addition, treatment with PPAR-gamma activators enhanced I kappa B concentrations in the cytoplasmic fractions and nuclear fractions from inflammatory myocardium. Concurrently, NF-kappa B was greatly activated in myocarditis; this activation was blocked in the 15d-PGJ(2) treated and PIO treated groups. Conclusions: PPAR-gamma may have a role in the pathophysiology of EAM. Because an increase in I kappa B expression and inhibition of translocation of the NF-kappa B subunit p65 to the nucleus in inflammatory cells correlated with the protective effects of PPAR-gamma activators, these results suggest that PPAR-gamma activators act sequentially through PPAR-gamma activation, I kappa B induction, blockade of NF-kappa B activation, and inhibition of inflammatory cytokine expression. These results suggest that PPAR-gamma activators such as 15d- PGJ(2) and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.