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DNMT1-PPAR? pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice.

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 (Tg(DNMT1)) or PPAR-? (Tg(PPAR-?)) 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-? pathway in regulating inflammatory cytokine production. We demonstrated that Tg(DNMT1) 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-? promoter was regulated by DNMT1 in macrophages. Notably, additional Tg(PPAR-?) or pharmacological activation of PPAR-? effectively prevented Tg(DNMT1)-induced proinflammatory cytokine production in macrophages and AS development in the mouse model. Finally, we demonstrated that elevated DNMT1 was correlated with decreased PPAR-?, 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.

SUBMITTER: Yu J

PROVIDER: S-EPMC4987643 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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DNMT1-PPARγ pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice.

Yu Jie J Qiu Youzhu Y Yang Jie J Bian Shizhu S Chen Guozhu G Deng Mengyang M Kang Huali H Huang Lan L

Scientific reports 20160817

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 (Tg(DNMT1)) or PPAR-γ (Tg(PPAR-γ)) to investigate their effects on AS progression in ApoE-knockout mice fed an atherogenic diet. Primary macropha ...[more]

PMID: 27530451

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Project description:ObjectiveTo investigate the mechanism of Connexin 37 (Cx37) and Kv1.3 pathways in atherosclerosis (AS).MethodsApoE-/- mice were given a high-fat diet to establish atherosclerosis (AS) model, and macrophages in mice were isolated and extracted to transfect Cx37 vectors with silencing or overexpressing, and Kv1.3 pathway blockers were used to inhibit the pathway activity. The indexes of body weight, blood glucose, and blood lipid of mice were collected. The protein and mRNA expression levels of Cx37 and Kv1.3 were detected by reverse transcription-PCR (RT-PCR), Western blot, and immunofluorescence technique. Oil red O staining was used to observe plaque area. Masson staining was used to detect collagen content. The concentrations of chemokine CCL7 were quantified using the ELISA kits. CCK8 was used to detect cell proliferation.ResultsCx37 and Kv1.3 were highly expressed in macrophages of AS mice, and the expression of Kv1.3 and CCL7 decreased after Cx37 was silenced, and the proliferation of macrophages was also decreased. Wild-type mice and AS model mice were treated with Cx37 overexpression vectors and Kv1.3 pathway blocking, and it was found that Cx37 overexpression could improve the blood lipid and blood glucose levels and increase the area of AS in AS mice. However, blocking the activity of Kv1.3 pathway can reduce the levels of blood lipid and blood glucose, increase the body weight of mice, and reduce the area of AS mice. Blocking the activity of Kv1.3 pathway can slow down the plaque development of AS mice and make its indexes close to wild-type mice. And the use of Kv1.3 pathway blockers on the basis of overexpression of Cx37 indicated that inhibition of Kv1.3 pathway activity did not affect the expression of Cx37, but could inhibit the collagen content in the plaque area of AS mice, inhibit the expression of chemokine CCL7, and reverse the effect of Cx37 overexpression.ConclusionCx37 can improve the activity of macrophages by regulating the expression of chemokines and the activity of Kv1.3 pathway in AS mice, and enrich macrophages in inflammatory tissues and expand the area of plaque formation.

Dataset Information

DNMT1-PPAR? pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice.

Publications

DNMT1-PPARγ pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice.

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