通过TET2-CYTB-ROS通路,TMAO诱导血管内皮细胞的灭
Linzhen Xia1,2,3, Zuo Wang2, Xiangyu Chen1,3
1Molecular Pathology Laboratory, Department of Pathology, Changsha Hospital for Maternal and Child Health Care, Hunan Normal University, Changsha, Hunan, People's Republic of China.
Journal of inflammation research
|July 7, 2025
概括
三甲基胺N-氧化物 (TMAO) 通过抑制TET2,增加活性氧物种 (ROS) 和促进血管内皮细胞 (VEC) 灭,降低细胞色素b (CYTB). 恢复CYTB水平可以抵消这些影响.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 生物化学 生物化学
背景情况:
- 血管内皮细胞 (VEC) 对血管完整性至关重要.
- 炎症性细胞死亡的一种亲炎症性形式,Pyroptosis,有助于各种血管疾病.
- 线粒体功能障碍和反应性氧物种 (ROS) 在VEC热中起着重要作用.
研究的目的:
- 为了研究细胞染色体b (CYTB) 在三甲基胺N氧化物 (TMAO) 诱导的VEC热中所起的调节作用.
- 阐明TMAO影响CYTB表达和随后的细胞事件的机制.
- 探索TET甲基细胞二氧化酶2 (TET2) 在该途径中的参与.
主要方法:
- 使用lentiviral载体对VEC进行操纵,以过度表达或沉默TET2和CYTB.
- 使用MitoSOX Red. 用于量化反应性氧物种 (ROS) 的水平.
- 通过 Hoechst 33342/PI 染色和 IL-1β 量化 (ELISA) 来评估热症.
- 蛋白质表达 (TET2,NLRP3,GSDMD,CYTB,Caspase-1) 被分析了西方的 blot.
- 通过qRT-PCR测量IL-1β,CYTB,ND2和TET2的mRNA水平.
- 用向双硫酸盐测序分析了基因促进物甲基化.
主要成果:
- TMAO治疗导致CYTB表达减少,ROS产量增加,并诱导VEC热和线粒体功能障碍.
- 过度表达CYTB抵消了TMAO的有害影响.
- 沉默CYTB加剧了mtROS的产生,而ROS清除剂 (MitoTEMPO) 抑制了热.
- TET2正调节了CYTB表达,而TMAO抑制了TET2,导致CYTB促进剂甲基化增加.
结论:
- TMAO通过抑制TET2促进CYTB基因促进物甲基化,并通过抑制TET2来降低CYTB表达的调节.
- 减少CYTB表达会诱导ROS的产生,从而促进VEC灭.
- 这一途径突出了在血管病理中连接TMAO,CYTB,TET2和VEC热的新机制.
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