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

Abstract

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.

Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis

“…In the first reaction, Hcy is catalyzed by methylcobalamin-containing methionine synthase (MS) to form methionine and tetrahydrofolate (THF) via receiving methyl from 5-methylTHF ( 16 ). Thus, Hcy metabolism generates cross-link with intracellular folate metabolism ( 17 ), which is also an important reason for folate level affect Hcy metabolism. In the second reaction, betaine-dependent remethylation backs Hcy to methionine by betaine-homocysteine methyltransferase (BHMT) ( 18 ).…”

Association between folic acid levels and sarcopenia in American adults: evidence from NHANES

“…In the short term, folate can bind to lead ions to form insoluble complexes, promoting the excretion and detoxi cation of lead [29]. Over the long term, folate affects DNA methylation, in uencing the expression of genes related to monocyte function and lead toxicity [30]. Animal studies suggest that folate not only affects lead metabolism but also protects against lead-induced oxidative damage [31].…”

TNC Accelerates Hypoxia-Induced Cardiac Injury in a METTL3-Dependent Manner

“…Our teams have also shown that, through modulating the maturation of miR-210 that targets AIFM3 mRNAs, it regulates cardiomyocyte health and the progression of cardiac dysfunction, implicating the differential regulations of miRNA biogenesis in cardiomyocytes under hypoxia [ 29 ]. Epigenetic regulations, not only including miRNAs, DNA methylation, and histone modification, have also been implicated in the myocardial protection process [ 41 , 42 ]. Recently, m 6 A methylation of RNA has also come into prominence as a new important mechanism regulating various biological processes [ 43 , 44 ].…”