Inhibiting DNA methylation by 5-Aza-2'-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation

Qiang Cao, Xianfeng Wang, Lin Jia, Ashis K. Mondal, Abdoulaye Diallo, Gregory A. Hawkins, Swapan K. Das, John S. Parks, Liqing Yu, Huidong Shi, Hang Shi, Bingzhong Xue

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

Inflammation marks all stages of atherogenesis. DNA hypermethylation in the whole genome or specific genes is associated with inflammation and cardiovascular diseases. Therefore, we aimed to study whether inhibiting DNA methylation by DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) ameliorates atherosclerosis in low-density lipoprotein receptor knockout (Ldlr-/-) mice. Ldlr-/- mice were fed an atherogenic diet and adminisered saline or 5-aza-dC (0.25 mg/kg) for up to 30 weeks. 5-aza-dC treatment markedly decreased atherosclerosis development in Ldlr-/- mice without changes inbodyweight, plasma lipid profile,macrophagecholesterol levels and plaque lipid content. Instead, this effect was associated with decreased macrophage inflammation. Macrophages with 5-aza-dC treatment had downregulated expression of genes involved in inflammation (TNF-α, IL-6, IL-1β, and inducible nitric oxidase) and chemotaxis (CD62/L-selectin, chemokine [C-C motif] ligand 2/MCP-1 [CCL2/MCP-1], CCL5, CCL9, and CCL2 receptor CCR2). This resulted in attenuated macrophage migration and adhesion to endothelial cells and reduced macrophage infiltration into atherosclerotic plaques. 5-aza-dC also suppressed macrophage endoplasmic reticulum stress, a key upstream signal that activates macrophage inflammation and apoptotic pathways. Finally, 5-aza-dC demethylated liver X receptor α (LXRα) and peroxisome proliferator-activated receptor γ1 (PPARγ1) promoters, which are both enriched with CpG sites. This led to overexpression of LXRα and PPARγ, which may be responsible for 5-aza-dC's antiinflammatory and atheroprotective effect. Our findings provide strong evidence that DNA methylation may play a significant role in cardiovascular diseases and serve as a therapeutic target for prevention and treatment of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)4925-4938
Number of pages14
JournalEndocrinology
Volume155
Issue number12
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Endocrinology

Fingerprint Dive into the research topics of 'Inhibiting DNA methylation by 5-Aza-2'-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation'. Together they form a unique fingerprint.

  • Cite this

    Cao, Q., Wang, X., Jia, L., Mondal, A. K., Diallo, A., Hawkins, G. A., Das, S. K., Parks, J. S., Yu, L., Shi, H., Shi, H., & Xue, B. (2014). Inhibiting DNA methylation by 5-Aza-2'-deoxycytidine ameliorates atherosclerosis through suppressing macrophage inflammation. Endocrinology, 155(12), 4925-4938. https://doi.org/10.1210/en.2014-1595