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 (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.

UV-induced DNA methyltransferase 1 promotes hypermethylation of tissue inhibitor of metalloproteinase 2 in the human skin

“…Silencing of DNMT1 prevented the activation of JAK2/STAT3 pathway via SOCS1 promoter in lipopolysaccharide-treated macrophages [39]. On other hand, overexpression of DNMT1 in macrophages led to proinflammatory cytokine production and atherosclerosis in a mouse model [40]. Moreover, since TIMPs and MMPs have been associated not only with photoaging and cancer [41], but also with inflammation, cell migration, cell proliferation, and apoptosis [6,7,27], our findings raise possibilities for therapeutic modalities in such fields using epigenetic modulations.…”

Dietary antioxidants remodel DNA methylation patterns in chronic disease

“…Another mode of action of vitamin E that is key for prevention of atherosclerosis/CVD, involves up‐regulation of PPARγ, a transcription factor with protective properties against oxidative stress (Tang et al, ). Interestingly, an animal study with transgenic mice with macrophage‐specific overexpression of DNMT1 demonstrates that DNA hypermethylation of the proximal PPARγ promoter was mediated by DNMT1 (Yu et al, ). Additionally, the luciferase activity of the unmethylated PPARγ promoter was significantly greater than that of the fully methylated promoter, indicating that PPARγ promoter activity is regulated by DNA methylation (Yu et al, ).…”

“…Interestingly, an animal study with transgenic mice with macrophage‐specific overexpression of DNMT1 demonstrates that DNA hypermethylation of the proximal PPARγ promoter was mediated by DNMT1 (Yu et al, ). Additionally, the luciferase activity of the unmethylated PPARγ promoter was significantly greater than that of the fully methylated promoter, indicating that PPARγ promoter activity is regulated by DNA methylation (Yu et al, ). Hence, since vitamin E down‐regulates DNMT1 expression (Huang et al, ), there is a possibility that vitamin E also mediates PPARγ up‐regulation indirectly by altering epigenetic regulation of PPARγ.…”

“…PPARγ promoter activity is regulated by DNA methylation (Yu et al, 2016). Hence, since vitamin E down-regulates DNMT1 expression (Huang et al, 2012), there is a possibility that vitamin E also medi- Stefanska, Salame, Bednarek, & Fabianowska-Majewska, 2012;Sun et al, 2018).…”

Potential epigenetic therapeutics for atherosclerosis treatment

“…RG108 is a non-nucleoside inhibitor which directly binds to the active site of DNMT1 and suppresses its activity. Considering the study by Yu et al [24] on the role of DNMT1 in atherosclerosis progression, inhibition of this enzyme by RG108 can be considered as a potential strategy to prevent or treat cardiovascular disease [24]. RG108 has been shown to effectively block DNMTs without covalent enzyme trapping in the human cell lines.…”