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

Abstract

To test the hypothesis that activation of peroxisome proliferator activated receptor gamma (PPAR-gamma) reduces experimental autoimmune myocarditis (EAM) associated with inhibitor kappaB (IkappaB) alpha induction, blockade of nuclear factor kappaB (NF-kappaB), and inhibition of inflammatory cytokine expression. EAM was induced in Lewis rats by immunisation with porcine cardiac myosin. PPAR-gamma activators 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2) and pioglitazone (PIO) were administered to rats with EAM. Enhanced PPAR-gamma expression was prominently stained in the nuclear and perinuclear regions of infiltrating inflammatory cells. Administration of 15d-PGJ2 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 IkappaB concentrations in the cytoplasmic fractions and nuclear fractions from inflammatory myocardium. Concurrently, NF-kappaB was greatly activated in myocarditis; this activation was blocked in the 15d-PGJ2 treated and PIO treated groups. PPAR-gamma may have a role in the pathophysiology of EAM. Because an increase in IkappaB expression and inhibition of translocation of the NF-kappaB 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, IkappaB induction, blockade of NF-kappaB activation, and inhibition of inflammatory cytokine expression. These results suggest that PPAR-gamma activators such as 15d-PGJ2 and PIO may have the potential to modulate human inflammatory heart diseases such as myocarditis.