Zhang Haimou, Qin Gangjian, Liang Gang, Li Jinan, Barrington Robert A, Liu Dong-Xu
Center for Infection and Immunity Research, School of Life Sciences, Hubei University, 11 XueYuan Road, Wuhan, Hubei, PR China.
Biochem Biophys Res Commun. 2007 Jun 1;357(2):446-52. doi: 10.1016/j.bbrc.2007.03.152. Epub 2007 Apr 2.
The complement system activation can mediate myocardial ischemia and reperfusion (I/R). Inhibition of C5a activity reveals attenuation of I/R-induced myocardial infarct size. However, the contribution of C5a receptor (C5aR) to I/R injury remains to be unknown. Here, we reported that both mRNA and protein for the C5aR were constitutively expressed on cardiomyocytes and upregulated as a function of time after I/R-induced myocardial cell injury in mice. Blockade of C5aR markedly decreased microvascular permeability in ischemic myocardial area and leukocyte adherence to coronary artery endothelium. Importantly, the blocking of C5aR with an anti-C5aR antibody was associated with inhibition in activation of protein kinase C delta (PKC-delta) and induction of PKC-mediated mitogen-activated protein kinase phosphatases-1 (MKP-1) leading to the increased activity of p42/p44 mitogen-activated protein (MAP) kinase cascade. These data provide evidence that C5aR-mediated myocardial cell injury is an important pathogenic factor, and that C5aR blockade may be useful therapeutic targets for the prevention of myocardial I/R injury.
补体系统激活可介导心肌缺血再灌注（I/R）。抑制C5a活性可使I/R诱导的心肌梗死面积减小。然而，C5a受体（C5aR）对I/R损伤的作用仍不清楚。在此，我们报道C5aR的mRNA和蛋白在心肌细胞上组成性表达，并在小鼠I/R诱导的心肌细胞损伤后随时间上调。阻断C5aR可显著降低缺血心肌区域的微血管通透性以及白细胞与冠状动脉内皮的黏附。重要的是，用抗C5aR抗体阻断C5aR与抑制蛋白激酶Cδ（PKC-δ）的激活以及诱导PKC介导的丝裂原活化蛋白激酶磷酸酶-1（MKP-1）有关，从而导致p42/p44丝裂原活化蛋白（MAP）激酶级联反应活性增加。这些数据证明C5aR介导的心肌细胞损伤是一个重要的致病因素，并且阻断C5aR可能是预防心肌I/R损伤的有用治疗靶点。
