Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
Cardiovasc Res. 2014 Sep 1;103(4):521-9. doi: 10.1093/cvr/cvu153. Epub 2014 Jun 15.
Early reperfusion is mandatory for the treatment of acute myocardial infarction. This process, however, also induces additional loss of viable myocardium, called ischaemia-reperfusion (IR) injury. Complement activation plays an important role in IR injury, partly through binding of C5a to its major receptor (C5aR). We investigated the role of C5aR on infarct size and cardiac function in a model for myocardial IR injury.
BALB/c (WT) mice and C5aR(-/-) mice underwent coronary occlusion for 30 min, followed by reperfusion. Infarct size, determined 24 h after IR, was reduced in C5aR(-/-) mice compared with WT mice (28.5 ± 2.1 vs. 35.7 ± 2.5%, P = 0.017). Bone marrow (BM) chimaera experiments showed that this effect was due to the absence of C5aR on circulating leucocytes, since a similar reduction in infarct size was observed in WT mice with C5aR-deficient BM cells (25.3 ± 2.2 vs. 34.6 ± 2.8%, P < 0.05), but not in C5aR(-/-) mice with WT BM cells. Reduced infarct size was associated with fewer neutrophils, T cells, and macrophages in the infarcted area 24 h after IR in C5aR(-/-) mice, and also with lower levels of Caspase-3/7 indicating less inflammation and apoptosis. Echocardiography 4 weeks after IR showed an improved ejection fraction in C5aR(-/-) mice (25.8 ± 5.5 vs. 19.2 ± 5.4%, P < 0.001).
The absence of C5aR on circulating leucocytes reduces infarct size, is associated with reduced leucocyte infiltration and with less apoptosis in the infarcted myocardium, and improves cardiac function in a mouse model of myocardial IR injury. Selective blocking of C5aR might be a promising strategy to prevent myocardial IR injury.
急性心肌梗死的治疗必须尽早恢复血运。然而，这一过程也会导致存活心肌的进一步损失，即缺血再灌注（IR）损伤。补体激活在 IR 损伤中起着重要作用，部分是通过 C5a 与其主要受体（C5aR）结合。我们在心肌 IR 损伤模型中研究了 C5aR 在梗死面积和心功能中的作用。
BALB/c（WT）小鼠和 C5aR（-/-）小鼠进行 30 分钟的冠状动脉闭塞，然后再灌注。IR 后 24 小时测定梗死面积，C5aR（-/-）小鼠的梗死面积小于 WT 小鼠（28.5±2.1%比 35.7±2.5%，P=0.017）。骨髓（BM）嵌合体实验表明，这种效应是由于循环白细胞中缺乏 C5aR，因为 WT 小鼠用缺乏 C5aR 的 BM 细胞后，梗死面积也有类似的减少（25.3±2.2%比 34.6±2.8%，P<0.05），但 C5aR（-/-）小鼠用 WT BM 细胞则没有。IR 后 24 小时，C5aR（-/-）小鼠梗死区的中性粒细胞、T 细胞和巨噬细胞减少，同时 Caspase-3/7 水平降低，表明炎症和细胞凋亡减少，与梗死面积减小相关。IR 后 4 周行超声心动图检查显示 C5aR（-/-）小鼠的射血分数改善（25.8±5.5%比 19.2±5.4%，P<0.001）。
循环白细胞中缺乏 C5aR 可减少梗死面积，与梗死心肌中白细胞浸润减少和细胞凋亡减少相关，并改善心肌 IR 损伤的小鼠心功能。选择性阻断 C5aR 可能是预防心肌 IR 损伤的一种有前途的策略。
