title: DNA methylation in cystathionine-γ-lyase (CSE) gene promoter induced by ox-LDL in macrophages and in apoE knockout mice.
abstract: Recent studies suggest that epigenetic alterations such as DNA methylation control many aspects of monocytes/macrophages and participate in the pathogenesis of atherosclerosis, a lipid-driven inflammatory disorder. Our and other groups demonstrated that dysregulation of cystathionine γ-lyase (CSE) -hydrogen sulfide (H2S) pathway was involved in monocyte/macrophages-mediated inflammation and atherosclerosis. However, it remains unknown whether altered cse methylation in macrophages may play a role in linking CSE-H2S dysregulation and atherosclerosis. In the present study, we showed that plasma H2S and H2S production in the peritoneal macrophages of apolipoprotein knockout (apoE(-/-)) mice gradually decreased with ages, and were also lower than that in control mice at 12 weeks older. Moreover, CSE mRNA expressions decreased while DNA methyltransferase (DNMT) expressions increased in the peritoneal macrophages isolated from apoE(-/-) mice, compared to age-matched wildtype mice. Similar observations were obtained in an in vitro study. In oxidized low-density lipoprotein (ox-LDL)-treated raw264.7 macrophages, cse transcription was down-regulated while the expression and activity of DNMT was up-regulated, associated with enhanced DNA methylation in cse promoter. Suppression of DNMT with its inhibitor or siRNA reversed the decrease of CSE mRNA. Therefore, our data suggest that DNA hypermethylation of CpG rich region in cse promoter might contribute to the decrease of cse transcription and H2S production in macrophages, and thus contribute to atherosclerosis development.
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Hua-Ping
authors.initials: HP
authors.lastname: Du
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: You
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Cao
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China; Department of Neurology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China. Electronic address: hulifang@suda.edu.cn.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Hu
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China; Department of Neurology, The Second Affiliated Hospital of Soochow University, Soochow University, Suzhou, Jiangsu 215021, China; Beijing Key Laboratory for Parkinson's Disease, Beijing 100053, China.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003542:Cystathionine gamma-Lyase / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics*; D006862:Hydrogen Sulfide / Q000097:blood*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000067996:RAW 264.7 Cells
chemical_list: D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: Atherosclerosis; Cystathionine γ-lyase; DNA methylation; Hydrogen sulfide; Macrophage; ox-LDL