Abstract
The DNA methyltransferase-mediated proinflammatory activation of macrophages is causally linked to the development of atherosclerosis (AS). However, the role of DNMT1, a DNA methylation maintenance enzyme, in macrophage polarization and AS development remains obscure. Here, we established transgenic mice with macrophage-specific overexpression of DNMT1 (TgDNMT1) or PPAR-γ (TgPPAR-γ) to investigate their effects on AS progression in ApoE-knockout mice fed an atherogenic diet. Primary macrophages were extracted to study the role of the DNMT1/PPAR-γ pathway in regulating inflammatory cytokine production. We demonstrated that TgDNMT1 significantly increased proinflammatory cytokine production in macrophages and plasma, and it accelerated the progression of AS in the atherogenic diet-treated ApoE-knockout mice. Further, we found that the DNA methylation status of the proximal PPAR-γ promoter was regulated by DNMT1 in macrophages. Notably, additional TgPPAR-γ or pharmacological activation of PPAR-γ effectively prevented TgDNMT1-induced proinflammatory cytokine production in macrophages and AS development in the mouse model. Finally, we demonstrated that elevated DNMT1 was correlated with decreased PPAR-γ, and increased proinflammatory cytokine production in the peripheral blood monocytes isolated from the patients with AS, compared to those of healthy donors. Our findings shed light on a novel strategy for the prevention and therapy of AS.
Highlights
Atherosclerosis (AS), a common disorder worldwide, is causally linked to complex diseases, including coronary heart disease and stroke[1,2,3]
The results showed that the mRNA levels of DNMT1, DNMT3a and DNMT3b were notably increased in the adipose tissue-derived macrophages (ATMs) from the mice fed a high fat diet (HFD), compared to those of mice fed a normal diet (Fig. 1a)
We found that the ApoE−/− mouse-derived ATMs expressed more proinflammatory cytokines (e.g., TNFα, IL-1βand IL-6) and fewer anti-inflammatory cytokines (e.g., IL-10 and Arg1) than those from the wild-type mice (Fig. 1c)
Summary
Atherosclerosis (AS), a common disorder worldwide, is causally linked to complex diseases, including coronary heart disease and stroke[1,2,3]. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) plays an important role in promoting the polarization of M2 macrophages[11,12]. Regulation of PPAR-γexpression or activity provides an effective means to manage inflammatory cytokine production by macrophages[11,12]. Emerging studies have focused on the role of gene expression in the regulation of macrophage activity[8,13,14]. The roles of DNA methyltransferases in macrophage polarization and AS development have not been fully elucidated. We hypothesized that DNMT1 could regulate inflammatory cytokine production in macrophages and affect the development of AS. To test this hypothesis, we established a mouse model with a macrophage-specific transgene of DNMT1 or PPAR-γ. Using in vitro and in vivo experiments, we identified the role of the DNMT1/PPAR-γpathway in the development of AS
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