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

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-gamma (Tg(PPAR-gamma)) 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-gamma 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-gamma promoter was regulated by DNMT1 in macrophages. Notably, additional Tg(PPAR-gamma) or pharmacological activation of PPAR-gamma 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-gamma, 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.