Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter.
Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter.
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DOI：
10.3390/ijms160612560
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发表时间：
2015-06-03
影响因子：
5.6
通讯作者：
Hu LF
中科院分区：
文献类型：
--
作者：
Li JJ;Li Q;Du HP;Wang YL;You SJ;Wang F;Xu XS;Cheng J;Cao YJ;Liu CF;Hu LF
高同型半胱氨酸血症（Hyperhomocysteinemia，HHcy）是动脉粥样硬化等心血管疾病的独立危险因素。不幸的是，发现降低Hcy的策略在减少心血管事件方面的作用有限。其潜在机制尚不清楚。越来越多的证据表明炎症在高同型半胱氨酸的发病机制中起作用。同型半胱氨酸（Homocysteine，Hcy）是硫化氢（hydrogen sulfide，H2S）的前体，是由胱硫醚β-合成酶和胱硫醚γ-裂解酶（cystathietrin γ-lyase，CSE）催化的转硫途径形成的，是一种新型的炎症调节剂。本研究发现，蛋氨酸可诱导小鼠轻度高同型半胱氨酸血症，并伴有血浆TNF-α和IL-1β水平升高，血浆H2S水平和腹腔巨噬细胞CSE表达降低。H2S释放化合物GYY 4137可抑制HHcy小鼠和Hcy处理的raw264.7细胞血浆中TNF-α和IL-1β的升高，而CSE抑制剂PAG则可使其升高;体外研究表明，Hcy可抑制巨噬细胞CSE表达和H2S产生，并伴有DNA甲基转移酶（DNMT）表达和cse启动子区DNA超甲基化的增加。DNMT抑制或敲低可逆转同型半胱氨酸诱导的巨噬细胞CSE转录的降低。总之，我们的研究结果表明，同型半胱氨酸可能通过抑制CSE-H2S信号转导，与增加启动子DNA甲基化和转录抑制cse在巨噬细胞中引发炎症。
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.
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DOI：
10.1126/science.1162667
发表时间：
2008-10-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Yang G;Wu L;Jiang B;Yang W;Qi J;Cao K;Meng Q;Mustafa AK;Mu W;Zhang S;Snyder SH;Wang R
通讯作者：
Wang R
硫化氢可减轻小鼠中脑内施用的同型半胱氨酸诱导的神经变性和神经血管功能障碍。
影响因子：
3.3
作者：
Kamat PK;Kalani A;Givvimani S;Sathnur PB;Tyagi SC;Tyagi N
通讯作者：
Tyagi N
DOI：
10.1073/pnas.1413390111
发表时间：
2014-09-16
影响因子：
11.1
作者：
Flannigan, Kyle L.;Agbor, Terence A.;Wallace, John L.
通讯作者：
Wallace, John L.
影响因子：
20.3
作者：
Jamaluddin, Md S.;Chen, Irene;Wang, Hong
通讯作者：
Wang, Hong
影响因子：
3.1
作者：
Jiang Yi-Deng;Sun Tao;Wang Shu-Ren
通讯作者：
Wang Shu-Ren