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Int. J. Mol. Sci. 2017, 18(5), 990; doi:10.3390/ijms18050990

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

1
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China
2
Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin 300052, China
*
Authors to whom correspondence should be addressed.
Academic Editors: Lorenza Speranza, Sara Franceschelli and José L. Quiles
Received: 19 March 2017 / Revised: 25 April 2017 / Accepted: 2 May 2017 / Published: 5 May 2017
(This article belongs to the Special Issue Correlation between Nutrition, Oxidative Stress and Disease)
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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. View Full-Text
Keywords: folic acid; DNA methylation; atherosclerosis; vascular endothelial growth factor; monocyte chemoattractant protein-1 folic acid; DNA methylation; atherosclerosis; vascular endothelial growth factor; monocyte chemoattractant protein-1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Cui, S.; Li, W.; Lv, X.; Wang, P.; Gao, Y.; Huang, G. Folic Acid Supplementation Delays Atherosclerotic Lesion Development by Modulating MCP1 and VEGF DNA Methylation Levels In Vivo and In Vitro. Int. J. Mol. Sci. 2017, 18, 990.

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