Highly Purified Eicosapentaenoic Acid Alleviates the Inflammatory Response and Oxidative Stress in Macrophages during Atherosclerosis via the miR‐1a‐3p/sFRP1/Wnt/PCP‐JNK Pathway

Abstract

Highly purified eicosapentaenoic acid (EPA) has shown great effects in the prevention of atherosclerosis. In a murine model, it significantly reduced plaque accumulation, lowered plasma lipid levels, and decreased inflammation levels, which was also observed <i>in vitro</i>. Using microRNA sequencing, we identified differentially expressed microRNAs, among which miR-1a-3p was selected for further validation. Overexpression of miR-1a-3p in RAW264.7 cells worsened lipid accumulation, increased oxidative stress, and exacerbated inflammatory responses whereas its downregulation produced the opposite results. Potential targets of miR-1a-3p were analyzed by prediction tools. Then, secreted frizzled-related protein 1 (sFRP1), an antagonist of the Wnt pathway, was confirmed as the target gene of miR-1a-3p by a dual-luciferase reporter assay. Further research showed that in macrophages, EPA influenced the activation of the Wnt/planar cell polarity-c-Jun N-terminal kinase (Wnt/PCP-JNK) axis, which is consistent with the phenomenon that miR-1a-3p has an impact on this same axis. Collectively, our findings suggest that EPA mitigates inflammatory responses and oxidative responses both <i>in vivo</i> and <i>in vitro</i> by targeting the miR-1a-3p/sFRP1/Wnt/PCP-JNK axis in macrophages, which may explain the cardioprotective role of EPA and promote the application of EPA in clinical practice.