Department of Cardiac Surgery, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, China.
Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Theranostics. 2021 Apr 3;11(12):5939-5954. doi: 10.7150/thno.58160. eCollection 2021.
We previously found that complement components are upregulated in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and inhibiting the complement receptor C5aR reduces disease severity in desmin knockout ( ) mice, a model for ARVC. Here, we examined the mechanism underlying complement activation in ARVC, revealing a potential new therapeutic target. First, immunostaining, RT-PCR and western blot were used to detect the expression levels of complement and coagulation factors. Second, we knocked out the central complement component C3 in mice (ARVC model) by crossing mice with mice to explore whether complement system activation occurs independently of the conventional pathway. Then, we evaluated whether a targeted intervention to coagulation system is effective to reduce myocardium injury. Finally, the plasma sC5b9 level was assessed to investigate the role in predicting adverse cardiac events in the ARVC cohort. The complement system is activated in the myocardium in ARVC. Autoantibodies against myocardial proteins provided a possible mechanism underlying. Moreover, we found increased levels of myocardial C5 and the serum C5a in mice compared to wild-type mice, indicating that C5 is activated independently from the conventional pathway, presumably via the coagulation system. Crosstalk between the complement and coagulation systems exacerbated the myocardial injury in ARVC mice, and this injury was reduced by using the thrombin inhibitor lepirudin. In addition, we found significantly elevated plasma levels of sC5b9 and thrombin in patients, and this increase was correlated with all-cause mortality. These results suggest that crosstalk between the coagulation and complement systems plays a pathogenic role in cardiac dysfunction in ARVC. Thus, understanding this crosstalk may have important clinical implications with respect to diagnosing and treating ARVC.
我们之前发现，心律失常性右心室心肌病（ARVC）患者的心肌中补体成分上调，抑制补体受体 C5aR 可降低肌联蛋白敲除（）小鼠（ARVC 的模型）的疾病严重程度。在这里，我们研究了 ARVC 中补体激活的机制，揭示了一个潜在的新治疗靶点。首先，通过免疫染色、RT-PCR 和 Western blot 检测补体和凝血因子的表达水平。其次，我们通过将 小鼠与 小鼠杂交，在 小鼠中敲除中央补体成分 C3（ARVC 模型），以探索补体系统激活是否独立于经典途径发生。然后，我们评估针对凝血系统的靶向干预是否有效减少心肌损伤。最后，评估血浆 sC5b9 水平以研究其在预测 ARVC 队列不良心脏事件中的作用。ARVC 中心肌中补体系统被激活。针对心肌蛋白的自身抗体提供了一种可能的潜在机制。此外，与野生型小鼠相比，我们发现 小鼠心肌中的 C5 和血清中的 C5a 水平升高，表明 C5 独立于经典途径激活，可能通过凝血系统。补体和凝血系统之间的串扰加剧了 ARVC 小鼠的心肌损伤，而使用凝血酶抑制剂 lepirudin 可减少这种损伤。此外，我们发现患者血浆中 sC5b9 和凝血酶水平显著升高，并且这种升高与全因死亡率相关。这些结果表明，凝血和补体系统之间的串扰在 ARVC 中的心脏功能障碍中发挥致病作用。因此，了解这种串扰可能对 ARVC 的诊断和治疗具有重要的临床意义。
