Fenofibrate prevents myocardial inflammation and fibrosis via PPAR&alpha;/I&kappa;B&zeta; signaling pathway in rat autoimmune myocarditis

Chang,He; Wang,Yue; Wu,Yang; Shi,Song-Lin; Qi,Zhi

doi:10.3892/etm.2025.12879

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

Authors:
- He Chang
- Yue Wang
- Yang Wu
- Song-Lin Shi
- Zhi Qi
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Affiliations: Department of Geriatrics, Xiang'an Hospital of Xiamen University, Xiamen, Fujian 361100, P.R. China, Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, Fujian 361102, P.R. China
Published online on: May 6, 2025 https://doi.org/10.3892/etm.2025.12879
Article Number: 128
Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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