Atheroprotective mechanism by which folic acid regulates monocyte subsets and function through DNA methylation

Clin Epigenetics. 2022 Feb 28;14(1):32. doi: 10.1186/s13148-022-01248-0.


Background: Recent studies have suggested that folic acid can restore abnormal DNA methylation and monocyte subset shifts caused by hyperhomocysteinemia (HHcy) and hyperlipidemia (HL). However, the exact mechanism of action is still not fully understood. In this study, we further investigated the reversal effect and underlying mechanism of folic acid on the shift in monocyte subsets induced by aberrant lipids and Hcy metabolism via DNA methylation in vitro and in vivo.

Results: Our results showed that intermediate monocytes were significantly increased but had the lowest global 5-methylcytosine (5-mC) levels in coronary artery disease (CAD) patients, which might lead to a decrease in the global 5-mC levels of peripheral blood leukocytes (PBLs). We also discovered that ARID5B might mediate the increased proportion of intermediate monocytes, as this factor was related to the proportion of monocyte subsets and the expression of CCR2. The expression of ARID5B was inversely associated with the hypermethylated cg25953130 CpG site, which was induced by HL and HHcy. ARID5B could also regulate monocyte CCR2, MCP-1, and TNF-α expression, adhesion and migration, macrophage polarization, and monocyte/macrophage apoptosis, which might explain the regulatory effect of ARID5B on monocyte subset shifting. Folic acid reversed HL- and HHcy-mediated aberrant global and cg25953130 DNA methylation, reduced the proportion of intermediate monocytes, and inhibited the formation of atherosclerotic plaques.

Conclusion: Folic acid plays a protective role against atherosclerosis through the regulation of DNA methylation, ARID5B expression, and monocyte subsets.

Keywords: ARID5B; Coronary artery disease; DNA methylation; Folic acid; Monocyte subsets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis* / genetics
  • Atherosclerosis* / metabolism
  • DNA Methylation
  • Folic Acid / metabolism
  • Folic Acid / pharmacology
  • Humans
  • Monocytes / metabolism
  • Plaque, Atherosclerotic* / genetics


  • Folic Acid