Atherosclerotic plaque rupture with subsequent mural thrombus formation is considered the main event compromising epicardial flow in acute myocardial infarction (AMI). However, the precise mechanisms underlying acute coronary occlusion are unknown.
We compared the proteomic profiles of systemic plasma and plasma derived from the site of thrombus formation of patients with AMI by two-dimensional gel electrophoresis and ELISA. We identified a local activation of the complement system, with selective accumulation of the complement activator Creactive protein (CRP) and the downstream complement effectors C3a and C5a. CRP in coronary thrombus co-localised with C1q and C3 immunoreactivities, suggesting classical complement activation. In vitro, coronary thrombus derived plasma enhanced neutrophil chemotaxis in a C5a dependent fashion. In vivo, neutrophil accumulation at the site of thrombus formation paralleled the time delay from symptom onset to first balloon inflation or aspiration, and was correlated with C5a and enzymatic infarct size. We present the first direct evidence for localised complement activation in acute coronary thrombi. Our data indicate that local complement effectors amplify the vascular occlusion process in AMI by enhanced neutrophil recruitment.
2
Adlbrecht C,
Bonderman D,
Plass C.
et al. Active endothelin is an important vasoconstrictor in acute coronary thrombi. Thromb Haemost 2007; 97: 642-649.
4
Lim P,
Collet JP,
Moutereau S.
et al. Fetuin-A is an independent predictor of death after ST-elevation myocardial infarction. Clin Chem 2007; 53: 1835-1840.
5
Ridker PM,
Rifai N,
Rose L.
et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 2002; 347: 1557-1565.
6
De Luca G,
Suryapranata H,
Zijlstra F.
et al. Symptom-onset-to-balloon time and mortality in patients with acute myocardial infarction treated by primary angioplasty. J Am Coll Cardiol 2003; 42: 991-997.
8
Wilson RF,
Laxson DD,
Lesser JR.
et al. Intense microvascular constriction after angioplasty of acute thrombotic coronary arterial lesions. Lancet 1989; 01: 807-811.
10
Lefevre T,
Garcia E,
Reimers B.
et al. X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: results of the X-sizer in AMI for negligible embolization and optimal ST resolution (X AMINE ST) trial. J Am Coll Cardiol 19-7 2005; 46: 246-252.
11
Verdeguer F,
Castro C,
Kubicek M.
et al. Complement regulation in murine and human hypercholesterolemia and role in the control of macrophage and smooth muscle cell proliferation. Cardiovasc Res 2007; 76: 340-350.
12
Katayama H,
Tabata T,
Ishihama Y.
et al. Efficient in-gel digestion procedure using 5-cyclohexyl-1-pentyl-beta-D-maltoside as an additive for gel-based membrane proteomics. Rapid Commun Mass Spectrom 2004; 18: 2388-2394.
13
Slany A,
Haudek VJ,
Gundacker NC.
et al. Introducing a new parameter for quality control of proteome profiles: consideration of commonly expressed proteins. Electrophoresis 2009; 30: 1306-1328.
14
Wimmer H,
Gundacker NC,
Griss J.
et al. Introducing the CPL/MUW proteome database: interpretation of human liver and liver cancer proteome profiles by referring to isolated primary cells. Electrophoresis 2009; 30: 2076-2089.
15
Lang IM,
Marsh JJ,
Olman MA.
et al. Expression of type 1 plasminogen activator inhibitor in chronic pulmonary thromboemboli. Circulation 1994; 89: 2715-2721.
16
Campregher C,
Luciani MG,
Gasche C.
Activated neutrophils induce an hMSH2-dependent G2/M checkpoint arrest and replication errors at a (CA)13-repeat in colon epithelial cells. Gut 2008; 57: 780-787.
18
Zhang B,
VerBerkmoes NC,
Langston MA.
et al. Detecting differential and correlated protein expression in label-free shotgun proteomics. J Proteome Res 2006; 05: 2909-2918.
20
Wolbink GJ,
Brouwer MC,
Buysmann S.
et al. CRP-mediated activation of complement in vivo: assessment by measuring circulating complement-Creactive protein complexes. J Immunol 1996; 157: 473-479.
21
Reynolds GD,
Vance RP.
C-reactive protein immunohistochemical localization in normal and atherosclerotic human aortas. Arch Pathol Lab Med 1987; 111: 265-269.
22
Lagrand WK,
Niessen HW,
Wolbink GJ.
et al. C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation 1997; 95: 97-103.
23
Nijmeijer R,
Lagrand WK,
Visser CA.
et al. CRP, a major culprit in complement-mediated tissue damage in acute myocardial infarction?. Int Immunopharmacol 2001; 01: 403-414.
24
Maier W,
Altwegg LA,
Corti R.
et al. Inflammatory markers at the site of ruptured plaque in acute myocardial infarction: locally increased interleukin-6 and serum amyloid A but decreased C-reactive protein. Circulation 2005; 111: 1355-1361.
25
Nienhuis MB,
Ottervanger JP,
de Boer MJ.
et al. Prognostic importance of creatine kinase and creatine kinase-MB after primary percutaneous coronary intervention for ST-elevation myocardial infarction. Am Heart J 2008; 155: 673-679.
27
Singh P,
Hoffmann M,
Wolk R.
et al. Leptin induces C-reactive protein expression in vascular endothelial cells. Arterioscler Thromb Vasc Biol 2007; 27: e302-e307.
28
Yasojima K,
Schwab C,
McGeer EG.
et al. Generation of C-reactive protein and complement components in atherosclerotic plaques. Am J Pathol 2001; 158: 1039-1051.
29
Kalowski S,
Howes Jr EL,
Margaretten W.
et al. Effects of intravascular clotting on the activation of the complement system: The role of the platelet. Am J Pathol 1975; 78: 525-536.
30
Griselli M,
Herbert J,
Hutchinson WL.
et al. C-reactive protein and complement are important mediators of tissue damage in acute myocardial infarction. J Exp Med 20-12 1999; 190: 1733-1740.
33
Weisman HF,
Bartow T,
Leppo MK.
et al. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science 1990; 249: 146-151.
37
Phillipson M,
Heit B,
Colarusso P.
et al. Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med 2006; 203: 2569-2575.
