PMID- 26047341 OWN - NLM STAT- MEDLINE DCOM- 20160222 LR - 20181113 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 16 IP - 6 DP - 2015 Jun 3 TI - Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter. PG - 12560-77 LID - 10.3390/ijms160612560 [doi] AB - 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 beta-synthase and cystathionine gamma-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-alpha and IL-1beta 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-alpha and IL-1beta 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. FAU - Li, Jiao-Jiao AU - Li JJ AD - 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. FAU - Li, Qian AU - Li Q AD - Institute of Neuroscience, Soochow University, Suzhou 215123, China. liqian90626@163.com. AD - Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215123, China. liqian90626@163.com. FAU - Du, Hua-Ping AU - Du HP AD - 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. FAU - Wang, Ya-Li AU - Wang YL AD - 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. AD - Institute of Neuroscience, Soochow University, Suzhou 215123, China. yjyali@sina.com. FAU - You, Shou-Jiang AU - You SJ AD - 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. FAU - Wang, Fen AU - Wang F AD - 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. AD - Institute of Neuroscience, Soochow University, Suzhou 215123, China. wangfen_1982@126.com. FAU - Xu, Xing-Shun AU - Xu XS AD - 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. FAU - Cheng, Jian AU - Cheng J AD - Institute of Neuroscience, Soochow University, Suzhou 215123, China. jiancheng8@hotmail.com. FAU - Cao, Yong-Jun AU - Cao YJ AD - 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. FAU - Liu, Chun-Feng AU - Liu CF AD - 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. AD - Institute of Neuroscience, Soochow University, Suzhou 215123, China. liucf@suda.edu.cn. FAU - Hu, Li-Fang AU - Hu LF AD - 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. AD - Institute of Neuroscience, Soochow University, Suzhou 215123, China. hulifang@suda.edu.cn. AD - Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215123, China. hulifang@suda.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150603 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (GYY 4137) RN - 0 (Inflammation Mediators) RN - 0 (Morpholines) RN - 0 (Organothiophosphorus Compounds) RN - 0LVT1QZ0BA (Homocysteine) RN - AE28F7PNPL (Methionine) RN - EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferases) RN - EC 4.4.1.1 (Cystathionine gamma-Lyase) RN - YY9FVM7NSN (Hydrogen Sulfide) SB - IM MH - Animals MH - Cells, Cultured MH - Cystathionine gamma-Lyase/*genetics/metabolism MH - DNA (Cytosine-5-)-Methyltransferases/metabolism MH - DNA Methylation/*drug effects MH - Gene Expression Regulation/drug effects MH - Homocysteine/*pharmacology MH - Hydrogen Sulfide/metabolism MH - Hyperhomocysteinemia/*chemically induced/immunology MH - Inflammation Mediators/*pharmacology MH - Macrophages/*drug effects/immunology/metabolism MH - Male MH - Methionine/administration & dosage/adverse effects MH - Mice MH - Morpholines/pharmacology MH - Organothiophosphorus Compounds/pharmacology MH - Promoter Regions, Genetic/drug effects MH - Signal Transduction/drug effects PMC - PMC4490461 OTO - NOTNLM OT - DNA methylation OT - cystathionine gamma-lyase OT - homocysteine OT - hydrogen sulfide OT - macrophage EDAT- 2015/06/06 06:00 MHDA- 2016/02/24 06:00 PMCR- 2015/06/01 CRDT- 2015/06/06 06:00 PHST- 2015/02/25 00:00 [received] PHST- 2015/04/23 00:00 [revised] PHST- 2015/05/20 00:00 [accepted] PHST- 2015/06/06 06:00 [entrez] PHST- 2015/06/06 06:00 [pubmed] PHST- 2016/02/24 06:00 [medline] PHST- 2015/06/01 00:00 [pmc-release] AID - ijms160612560 [pii] AID - ijms-16-12560 [pii] AID - 10.3390/ijms160612560 [doi] PST - epublish SO - Int J Mol Sci. 2015 Jun 3;16(6):12560-77. doi: 10.3390/ijms160612560.