The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP-1 and MMP-9 in human macrophages in vitro.
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.
Speidl
Walter S
WS
Department of Internal Medicine II, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Kastl
Stefan P
SP
Hutter
Randolph
R
Katsaros
Katharina M
KM
Kaun
Christoph
C
Bauriedel
Gerhard
G
Maurer
Gerald
G
Huber
Kurt
K
Badimon
Juan J
JJ
Wojta
Johann
J
D002478:Cells, Cultured; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009637:Masoprocol / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism
C492910:6-amino-4-(4-n-pentyloxy)phenethylaminoquinazoline; D016328:NF-kappa B; D011799:Quinazolines; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D009637:Masoprocol; D015936:Complement C5a; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1