Maternal Diet Supplemented with Methyl-Donors Protects against Atherosclerosis in F1 ApoE−/− Mice

Colin Delaney,Sanjay K Garg,Chris Fernandes,Mark Hoeltzel,Robert H Allen,Raymond Yung,Sally Stabler,Cordula M Stover

doi:10.1371/journal.pone.0056253

Colin Delaney, Sanjay K Garg + Show 6 more

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https://doi.org/10.1371/journal.pone.0056253

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Abstract

Atherosclerosis is an inflammatory condition of the arterial wall mediated by cells of both innate and adaptive immunity. T lymphocytes play an important role in orchestrating the pathogenic immune response involved in the acceleration of atherosclerosis. Previously, we have shown that a prenatal methyl-donor supplementation diet (MS), when fed to dams during pregnancy and lactation, decreased the T cell-mediated pro-inflammatory cytokine and chemokine response in F1 mice. In the current study, we report feeding Apolipoprotein E (ApoE−/−) deficient dams with the MS diet during pregnancy reduces atherosclerotic plaques in F1 mice that were fed high fat diet (HFD) after weaning. F1 mice from dams on the MS diet exhibited increased global T cell DNA methylation. T-cell chemokines and their receptors (in particular CCR2, CCR5, and CXCR3) play important roles in the inflammatory cell recruitment to vascular lesions. MS diet significantly reduced Ccr2 mRNA and protein expression in CD3+ T cells but not in CD11b+ monocytes in MS F1 mice relative to controls. F1 litter size, HFD consumption, body weight, and body fat were similar between control and MS diet groups. Moreover, serum thiol metabolite levels were similar between the two groups. However, MS diet is associated with significantly higher serum HDL and lower LDL+VLDL levels in comparison to F1 mice from dams on the control diet. Inflammatory cytokines (IL-17, TNF-α, IL-6) were also lower in MS F1 mice serum and conditioned media from T-cell culture. Altogether, these data suggest that the MS diet ameliorates development of atherosclerosis by inhibiting the T-cell Ccr2 expression, reducing inflammatory cytokines production and increasing serum HDL:LDL ratio.

Highlights

Atherosclerosis is a chronic disease that remains asymptomatic for decades [1]
We have previously demonstrated that prenatal diet supplementation with metabolites of the DNA methylation cycle increases global DNA methylation in T cells, decreases inflammatory cytokine release in mice and decreases the response to chemokine signaling in vtiro and in vivo without altering total CD3+ T cell number [18]
By 34 wk of age, atheroma size in methyl-donor supplementation diet (MS) or control F1 mice were similar, suggesting that prenatal epigeneticmediated protection can be diminished by chronic exposure to postnatal high fat diet

Summary

Introduction

Several pathogenic mechanisms have been proposed that contribute to the development of atherosclerosis Both the pro-inflammatory cytokine (TNF-a, IFN-c, IL-1, IL-6, IL-8, IL-17) and chemokine (CCR2, CCR5, MCP-1) systems are involved in the process [2,3,4,5,6,7]. Abnormal metabolism such as hyperlipidemia and hyperhomocysteinemia is associated with disease progression [8]. Pro-inflammatory cytokines, low folate intake, and hypercholesterolemia have been shown to alter the pattern of DNA methylation via epigenetic mechanism [9,10]

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