title: DNMT1-PPARγ 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-γ (Tg(PPAR-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 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-γ promoter was regulated by DNMT1 in macrophages. Notably, additional Tg(PPAR-γ) or pharmacological activation of PPAR-γ 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-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.
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Youzhu
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Shizhu
authors.initials: S
authors.lastname: Bian
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Chen
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Mengyang
authors.initials: M
authors.lastname: Deng
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Huali
authors.initials: H
authors.lastname: Kang
authors.affiliation: Institute of Cardiovascular Diseases of the PLA , Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000074085:Mice, Knockout, ApoE; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D016207:Cytokines; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619381:Dnmt1 protein, mouse