Folic Acid Supplementation Delays Atherosclerotic Lesion Development by Modulating MCP1 and VEGF DNA Methylation Levels In Vivo and In Vitro

Abstract

The pathogenesis of atherosclerosis has been partly acknowledged to result from aberrant epigenetic mechanisms. Accordingly, low folate levels are considered to be a contributing factor to promoting vascular disease because of deregulation of DNA methylation. We hypothesized that increasing the levels of folic acid may act via an epigenetic gene silencing mechanism to ameliorate atherosclerosis. Here, we investigated the atheroprotective effects of folic acid and the resultant methylation status in high-fat diet-fed ApoE knockout mice and in oxidized low-density lipoprotein-treated human umbilical vein endothelial cells. We analyzed atherosclerotic lesion histology, folate concentration, homocysteine concentration, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH), and DNA methyltransferase activity, as well as monocyte chemotactic protein-1 (MCP1) and vascular endothelial growth factor (VEGF) expression and promoter methylation. Folic acid reduced atherosclerotic lesion size in ApoE knockout mice. The underlying folic acid protective mechanism appears to operate through regulating the normal homocysteine state, upregulating the SAM: SAH ratio, elevating DNA methyltransferase activity and expression, altering MCP1 and VEGF promoter methylation, and inhibiting MCP1 and VEGF expression. We conclude that folic acid supplementation effectively prevented atherosclerosis by modifying DNA methylation through the methionine cycle, improving DNA methyltransferase activity and expression, and thus changing the expression of atherosclerosis-related genes.

Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

“…A high level of homocysteine in the blood seems to provoke endothelial cell injury; this leads to inflammation in the blood vessels and accelerates atherogenesis, which can result in ischemic injury. Several studies of homocysteine-lowering treatments have shown a favorable effect on vascular pathologies associated with hyperhomocysteinemia [ 257 , 263 , 264 ]. However, other studies and meta-analyses have demonstrated that lowering homocysteine using B vitamins had no significant effect on stroke prevention [ 260 , 261 , 265 , 266 ], prevention of myocardial infarction [ 260 , 261 , 266 , 267 , 268 , 269 , 270 ], individual or global cognitive function [ 271 , 272 , 273 ], or other pathological conditions [ 274 , 275 , 276 ].…”

Hydrogen sulfide lowers hyperhomocysteinemia dependent on cystathionine γ lyase S‐sulfhydration in ApoE‐knockout atherosclerotic mice

“…High levels of homocysteine can induce oxidative stress, inflammation, ER stress, and epigenetic changes, cause endothelial dysfunction (Lai & Kan, ) and vascular smooth muscle cell dysplasia (Luo et al, ), and accelerate thrombosis (Dionisio, Jardin, Salido, & Rosado, ) and foam cell formation (Chernyavskiy, Veeranki, Sen, & Tyagi, ), thus promoting atherogenesis. Although some studies have shown that folic acid supplementation reduced atherosclerotic plaque size in ApoE‐knockout mice (Cui et al, ) or LDL receptor‐knockout mice (Pan et al, ), it did not reduce early atherosclerosis with HHcy in humans (Cacciapuoti, ). H 2 S donors per se can decrease atherosclerosis.…”

miR-148a-3p inhibits DNMT1-mediated methylation of VEGF and promotes proliferation and invasion in glioma cells via the PI3K/Akt/eNOS signaling pathway

“…Hypermethylation of VEGF and VEGF silencing can inhibit the carcinogenic effect of VEGF and the progress of gastric cancer [15]. Cui S et al has reported that DNA Methylation levels of VEGF in atherosclerotic were upregulated, and folic acid supplementation delays atherosclerotic lesion development by modulating VEGF DNA methylation levels in vivo and vitro [17]. These studies are consistent with our results, further con rming our hypothesis that VEGF methylation plays a vital role in the occurrence and development of cancer, and we can improve disease by increasing the methylation level of VEGF.…”

“…Other evidence suggests that the expression of VEGF is regulated by its methylation, hypermethylation of VEGF caused a decrease in the expression of mRNA [15,16]. In atherosclerotic, folic acid reduced atherosclerotic lesion through elevating DNA methyltransferase activity and expression, altering MCP1 and VEGF promoter methylation, and inhibiting MCP1 and VEGF expression [17]. The expression of VEGF was signi cant up-regulated in human glioma via [18,19].…”