机构：[1]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[2]Institute of Neuroscience, Soochow University, Suzhou 215123, China[3]Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215123, China
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-1 beta 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-1 beta 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.
基金：
This work was supported by Suzhou Medical Key Discipline Project, Science and Education
Methodist Youth Science and Technology Project of Suzhou Health Bureau (KJXW2011010) and
Suzhou Science and Technology Development Program (SYSD2013091, SZS201205). This was also
partly supported by the Start-up Funding for Imported Overseas Talents of Soochow University
(Q421500210) and the Priority Academic Program Development of Jiangsu Higher Education
Institutions (PAPD).
第一作者机构：[1]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
共同第一作者：
通讯作者：
通讯机构：[1]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[2]Institute of Neuroscience, Soochow University, Suzhou 215123, China[3]Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou 215123, China
推荐引用方式(GB/T 7714)：
Jiao-Jiao Li,Qian Li,Hua-Ping Du,et al.Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter[J].INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES.2015,16(6):12560-77.doi:10.3390/ijms160612560.
APA：
Jiao-Jiao Li,Qian Li,Hua-Ping Du,Ya-Li Wang,Shou-Jiang You...&Li-Fang Hu.(2015).Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter.INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES,16,(6)
MLA：
Jiao-Jiao Li,et al."Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter".INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 16..6(2015):12560-77
