Abstract 1190: The Complement Component C5a is Present in Human Unstable Coronary Lesions in Vivo and Induces the Expression of MMP-9 in Human Macrophages via Nf-kappaB Activation In Vitro
Background. The complement component C5a formed during activation of the complement cascade exerts chemotactic and proinflammatory effects. We have recently shown that serum levels of C5a predict cardiovascular risk in patients with advanced atherosclerosis. However, it is not known whether C5a may play an active role in the onset of acute coronary events.
Methods and Results. Immunohistochemical analysis of human coronary plaques obtained by atherectomy demonstrated the presence of C5a in macrophage rich areas and the necrotic core. Unstable plaques (n=9) showed significantly higher staining for C5a than stable coronary lesions (n=10; p<0.05). Double-labeling studies demonstrated colocalization of C5a and MMP-9. When human monocyte derived macrophages were stimulated in vitro with rhC5a, MMP-9 mRNA levels were increase 6-fold. In addition, MMP-9 antigen as detected by ELISA and MMP-9 activity as detected by a specific activity assay significantly increased after stimulation with rhC5a. Nuclear shift assay revealed that rhC5a stimulated NF-κB DNA binding and the NF-κB inhibitor 6-amino-4-phenoxyphenethylaminoquinazoline blocked the up-regulation of MMP-9 by rhC5a.
Conclusion. C5a is increased in unstable coronary plaques, colocalizes with MMP-9 and induces the expression of MMP-9 in human macrophages via NF-κB activation. Taken this observations together, activation of the complement cascade and formation of C5a may be involved in the onset of acute coronary events.