title: Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter.
abstract: Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine β-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1β in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1β in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. dragonrabbit@163.com.
authors.forename: Jiao-Jiao
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou 215123, China. liqian90626@163.com.|Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215123, China. liqian90626@163.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. duhuaping226@126.com.
authors.forename: Hua-Ping
authors.initials: HP
authors.lastname: Du
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. yjyali@sina.com.|Institute of Neuroscience, Soochow University, Suzhou 215123, China. yjyali@sina.com.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. 0319503013@163.com.
authors.forename: Shou-Jiang
authors.initials: SJ
authors.lastname: You
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. wangfen_1982@126.com.|Institute of Neuroscience, Soochow University, Suzhou 215123, China. wangfen_1982@126.com.
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. xingshunxu@hotmail.com.
authors.forename: Xing-Shun
authors.initials: XS
authors.lastname: Xu
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou 215123, China. jiancheng8@hotmail.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. yongjuncao@126.com.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Cao
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. liucf@suda.edu.cn.|Institute of Neuroscience, Soochow University, Suzhou 215123, China. liucf@suda.edu.cn.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
authors.affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. hulifang@suda.edu.cn.|Institute of Neuroscience, Soochow University, Suzhou 215123, China. hulifang@suda.edu.cn.|Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215123, China. hulifang@suda.edu.cn.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Hu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003542:Cystathionine gamma-Lyase / Q000235:genetics* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006710:Homocysteine / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000139:chemically induced* / Q000276:immunology; D018836:Inflammation Mediators / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000009:adverse effects; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009946:Organothiophosphorus Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C529376:GYY 4137; D018836:Inflammation Mediators; D009025:Morpholines; D009946:Organothiophosphorus Compounds; D006710:Homocysteine; D008715:Methionine; D004248:DNA (Cytosine-5-)-Methyltransferases; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide
keywords: DNA methylation; cystathionine γ-lyase; homocysteine; hydrogen sulfide; macrophage