Fenofibrate prevents myocardial inflammation and fibrosis via PPARα/IκBζ signaling pathway in rat autoimmune myocarditis

Fenofibrate is a peroxisome proliferator-activated receptor α (PPARα) agonist currently utilized clinically to reduce lipid levels. Experimental autoimmune myocarditis (EAM) is a T cell-mediated autoimmune myocarditis with histopathological evidence of extensive inflammatory cells infiltrated into the myocardium, resulting in myocardial fibrosis. Previously, the authors demonstrated that long-term fenofibrate could alleviate rat EAM; however, the underlying mechanism remains unclear. In the present study, EAM was induced in rats and fenofibrate was administered to evaluate its short-term effects. The CD4(+) T cells were purified from rats with EAM and PPARα (-/-) mice and determined the levels of IκBζ, pNF-κBp65 and IL-6. The findings of the present study revealed that fenofibrate treatment improved the progression of EAM in rats, as evidenced by a decreased ratio of the heart weight to body weight, reduced inflammatory cell infiltration, and relieved cardiac function. It also inhibited the transcription levels of T helper 17 (Th17)-related inflammatory cytokines, fibrosis-associated factors, and the expression of IκBζ, and dose-dependently downregulated IκBζ expression in differentiated Th17 cells from rats with EAM. The PPARα antagonist MK886 could reverse the effects in a dose-dependent manner. PPARα deficiency significantly upregulated IκBζ and pNF-κBp65 expression in the CD4(+) T cells of PPARα (-/-) mice. PPARα activation by three different PPARα agonists significantly inhibited IκBζ and IL-6 levels. The results suggested that IκBζ plays an important role in the pathogenesis of autoimmune myocarditis, and fenofibrate treatment ameliorates EAM by preventing myocardial inflammation and fibrosis, possibly through the PPARα/IκBζ signaling pathway.