Abstract
Macrophage is considered as a critical driving factor in the progression of atherosclerosis (AS), and epigenetic heterogeneity contributes important mechanisms in this process. Here, we identified that a histone demethylase jumonji domain-containing protein 1C (JMJD1C) is a promising biomarker for atherosclerotic cerebral infarction through clinical analysis. Then, AOPE-/- mice fed with a high fat diet and RAW264.7 cells induced by oxidized low-density lipoprotein (ox-LDL) were used as AS models to verify the function of JMJD1C in AS development in vivo and in vitro. JMJD1C knockdown significantly reduced plaque area, inflammation and endothelial damage in AS model mice, and also alleviated foam cell formation, inflammatory cytokines production and cell apoptosis in ox-LDL-treated RAW264.7 cells. Mechanistically, JMJD1C promoted the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9) through mediating H3 Lysine 9 demethylation. The effects of JMJD1C knockdown on ox-LDL-induced macrophages were blocked by PCSK9 overexpression. Altogether, our study proves that JMJD1C advances macrophage foam cell formation, inflammation and apoptosis to accelerate AS progression through H3 demethylation of PCSK9. The findings underscore the important role of JMJD1C-mediated histone modification in macrophage regulation and AS progression, which brings a new insight into the pathobiology of AS.
Published Version
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