Chen Yejia, Li Xiaobo, Lin Xinxin, Liang Hongbin, Liu Xuewei, Zhang Xinlu, Zhang Qiuxia, Zhou Fengyun, Yu Chen, Lei Li, Xiu Jiancheng
Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, China.
Thromb J. 2022 Apr 29;20(1):24. doi: 10.1186/s12959-022-00384-0.
Thrombotic events cannot be completely prevented by antithrombotics, implicating a therapeutic gap due to inflammation, a not yet sufficiently addressed mechanism. Neutrophil extracellular traps (NETs) are an essential interface between inflammation and thrombosis, but exactly how the NETotic process is initiated and maintained during arterial thrombosis remains incompletely understood.
We found that the plasma concentrations of C5a were higher in patients with ST-elevation myocardial infarction (STEMI) than in patients with angina and higher in mice with left common carotid artery (LCCA) thrombosis induced by FeCl than in control mice. We observed that the thrombus area and weight were decreased and that NET formation in the thrombi was reduced in the group treated with the selective C5aR1 receptor inhibitor PMX53 compared with the NaCl group. In vitro, NETosis was observed when C5a was added to neutrophil cultures, and this effect was reversed by PMX53. In addition, our data showed that C5a increased the production of mitochondrial reactive oxygen species (ROS) and that the promotion of NET formation by C5a was mitochondrial ROS (Mito-ROS) dependent. Furthermore, we found that C5a induced the production of Mito-ROS by inhibiting mitochondrial STAT3 activity.
By inhibiting mitochondrial STAT3 to elicit Mito-ROS generation, C5a triggers the generation of NETs to promote the development of arterial thrombosis. Hence, our study identifies complement C5a as a potential new target for the treatment and prevention of thrombosis.
抗血栓药物无法完全预防血栓形成事件，这意味着存在因炎症导致的治疗缺口，而炎症这一机制尚未得到充分研究。中性粒细胞胞外诱捕网（NETs）是炎症与血栓形成之间的重要界面，但在动脉血栓形成过程中，NETs形成过程究竟如何启动和维持仍不完全清楚。
我们发现，ST段抬高型心肌梗死（STEMI）患者血浆中C5a的浓度高于心绞痛患者，用氯化铁诱导左颈总动脉（LCCA）血栓形成的小鼠血浆中C5a的浓度高于对照小鼠。我们观察到，与氯化钠组相比，用选择性C5aR1受体抑制剂PMX53治疗的组中，血栓面积和重量减小，血栓中NETs的形成减少。在体外，当向中性粒细胞培养物中添加C5a时可观察到NETs形成，而PMX53可逆转这种作用。此外，我们的数据表明，C5a增加了线粒体活性氧（ROS）的产生，且C5a对NETs形成的促进作用依赖于线粒体ROS（Mito-ROS）。此外，我们发现C5a通过抑制线粒体STAT3活性诱导Mito-ROS的产生。
C5a通过抑制线粒体STAT3引发Mito-ROS生成，从而触发NETs的生成以促进动脉血栓形成的发展。因此，我们的研究确定补体C5a是治疗和预防血栓形成的潜在新靶点。
