Department of Hematology, the 3rd Xiangya Hospital, Central South University, Changsha, 410000, PR China.
Department of Hematology, the 3rd Xiangya Hospital, Central South University, Changsha, 410000, PR China.
Thromb Res. 2019 May;177:110-116. doi: 10.1016/j.thromres.2019.02.028. Epub 2019 Feb 23.
Trimethylamine-N-oxide (TMAO), one of the products in choline metabolite, is recently reported to be associated with cardiovascular diseases (CVD) that mainly attribute to atherothrombosis. However, the mechanisms how TMAO functions in the pathogenesis of CVD and atherothrombosis remain elusive. Tissue factor (TF) has been implicated in the thrombogenicity of atherosclerotic plaques. In the present study, we demonstrated that TMAO promoted TF (but not TF pathway inhibitor) expression via activation of NF-κB signaling pathway in primary human coronary artery endothelial cells (HCAECs). TMAO strongly increased TF activity and thrombin production. Further, a small dose of TMAO significantly increased TF expression and nuclear translocation of NF-κB with the synergistic action of low-dose of pro-atherosclerotic factors, such as TNF-α and HMGB1. Importantly, plasma TMAO level was positively correlated with TF activity in patients with ST-elevation myocardial infarction (STEMI). Altogether, our data revealed that TMAO promoted thrombosis through increasing TF expression and activity. The understanding of the new link between TMAO and atherothrombosis may facilitate therapeutic strategy in the prevention and treatment of atherothrombosis.
三甲基胺 N-氧化物（TMAO）是胆碱代谢物的产物之一，最近有报道称其与心血管疾病（CVD）有关，主要归因于动脉粥样血栓形成。然而，TMAO 在 CVD 和动脉粥样血栓形成发病机制中的作用机制仍不清楚。组织因子（TF）已被认为与动脉粥样硬化斑块的血栓形成有关。在本研究中，我们证明 TMAO 通过激活 NF-κB 信号通路在原代人冠状动脉内皮细胞（HCAEC）中促进 TF（但不是 TF 途径抑制剂）的表达。TMAO 强烈增加 TF 活性和凝血酶产生。此外，小剂量 TMAO 与促动脉粥样硬化因子（如 TNF-α和 HMGB1）的低剂量协同作用，可显著增加 TF 表达和 NF-κB 的核易位。重要的是，ST 段抬高型心肌梗死（STEMI）患者的血浆 TMAO 水平与 TF 活性呈正相关。总之，我们的数据表明 TMAO 通过增加 TF 表达和活性促进血栓形成。对 TMAO 与动脉粥样血栓形成之间新联系的理解可能有助于预防和治疗动脉粥样血栓形成的治疗策略。
