Department of Internal Medicine II, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
FASEB J. 2011 Jan;25(1):35-44. doi: 10.1096/fj.10-156083. Epub 2010 Sep 2.
The complement component C5a is formed during activation of the complement cascade and exerts chemotactic and proinflammatory effects. Macrophages, which are localized in the rupture-prone shoulder regions of coronary plaques, are thought to play a major role in plaque destabilization and rupture through the production of matrix metalloproteinases (MMPs). When human monocyte-derived macrophages were stimulated in vitro with C5a, MMP-1 and MMP-9 mRNA levels were significantly increased. Furthermore, C5a up-regulated MMP-1 and MMP-9 antigens and activity, as determined by ELISA and specific activity assays. These effects were blocked by antibodies against the receptor C5aR/CD88. In addition, blocking experiments revealed that MMP-1 expression was mediated by activation of the transcription factor AP-1, and MMP-9 expression was induced by activation of NF-κB and AP-1. Immunohistochemical analysis of human coronary plaques demonstrated the colocalization of C5a, MMP-1, and MMP-9 in vivo. Together, these observations indicate that activation of the complement cascade and formation of C5a may play a role in the onset of acute coronary events by induction of MMPs in atherosclerotic lesions.
补体成分 C5a 在补体级联激活过程中形成，并发挥趋化和促炎作用。巨噬细胞定位于易破裂的冠状动脉斑块肩部区域，通过产生基质金属蛋白酶 (MMPs) 被认为在斑块不稳定和破裂中起主要作用。当体外用人单核细胞衍生的巨噬细胞用 C5a 刺激时，MMP-1 和 MMP-9 mRNA 水平显著增加。此外，通过 ELISA 和特定活性测定法确定，C5a 上调了 MMP-1 和 MMP-9 抗原和活性。这些作用被针对受体 C5aR/CD88 的抗体阻断。此外，阻断实验表明 MMP-1 表达是通过转录因子 AP-1 的激活介导的，而 MMP-9 表达是通过 NF-κB 和 AP-1 的激活诱导的。对人类冠状动脉斑块的免疫组织化学分析表明，C5a、MMP-1 和 MMP-9 在体内共定位。总之，这些观察结果表明，补体级联的激活和 C5a 的形成可能通过在动脉粥样硬化病变中诱导 MMPs 而在急性冠状动脉事件的发生中起作用。
