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

Xin Lv,Guowei Huang,Yuxia Gao,Pengyan Wang,Shanshan Cui,Wen Li

doi:10.3390/ijms18050990

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.

Highlights

Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality in developed and developing countries [1]
The majority of DNA methylation occurs through DNA methyltransferases (DNMTs) which catalyze the addition of a methyl group to the C5 position of cytosine residues [8]
To determine whether folic acid ameliorates the progression of atherosclerosis, we assessed lipid deposition in the aortic sinus of mice using Oil-Red O staining and stained with hematoxylin-eosin (HE) for morphology of the atherosclerotic lesions in aorta arch

Summary

Introduction

Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality in developed and developing countries [1]. Atherosclerosis (AS), a complex multifactorial cardiovascular disease, is an inflammatory disease characterized by initial lipid deposition [1,2]. When endothelial cells are damaged, various cytokines produced by the arterial wall participate in the initiation and progression of an inflammatory reaction. Various studies have analyzed the involvement of epigenetic mechanisms in the development and progression of CVDs. a DNA methylation map of human AS has revealed differentially methylated Cytosine-phosphate-guanines (CpGs) are associated with AS onset as well as with endothelial and smooth muscle function [5,6,7]. DNA methylation in promoter regions is associated with changes in gene expression and silencing and aberrant DNA methylation may underlie CVD pathogenesis [9,10]

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Results

Conclusion