title: Leucocyte expression of complement C5a receptors exacerbates infarct size after myocardial reperfusion injury.
abstract: OBJECTIVE
  Early reperfusion is mandatory for the treatment of acute myocardial infarction. This process, however, also induces additional loss of viable myocardium, called ischaemia-reperfusion (IR) injury. Complement activation plays an important role in IR injury, partly through binding of C5a to its major receptor (C5aR). We investigated the role of C5aR on infarct size and cardiac function in a model for myocardial IR injury.
  
  
  RESULTS
  BALB/c (WT) mice and C5aR(-/-) mice underwent coronary occlusion for 30 min, followed by reperfusion. Infarct size, determined 24 h after IR, was reduced in C5aR(-/-) mice compared with WT mice (28.5 ± 2.1 vs. 35.7 ± 2.5%, P = 0.017). Bone marrow (BM) chimaera experiments showed that this effect was due to the absence of C5aR on circulating leucocytes, since a similar reduction in infarct size was observed in WT mice with C5aR-deficient BM cells (25.3 ± 2.2 vs. 34.6 ± 2.8%, P < 0.05), but not in C5aR(-/-) mice with WT BM cells. Reduced infarct size was associated with fewer neutrophils, T cells, and macrophages in the infarcted area 24 h after IR in C5aR(-/-) mice, and also with lower levels of Caspase-3/7 indicating less inflammation and apoptosis. Echocardiography 4 weeks after IR showed an improved ejection fraction in C5aR(-/-) mice (25.8 ± 5.5 vs. 19.2 ± 5.4%, P < 0.001).
  
  
  CONCLUSIONS
  The absence of C5aR on circulating leucocytes reduces infarct size, is associated with reduced leucocyte infiltration and with less apoptosis in the infarcted myocardium, and improves cardiac function in a mouse model of myocardial IR injury. Selective blocking of C5aR might be a promising strategy to prevent myocardial IR injury.
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Vince C
authors.initials: VC
authors.lastname: De Hoog
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Timmers
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Amerik
authors.initials: A
authors.lastname: Van Duijvenvoorde
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: De Jager
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Van Middelaar
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Mirjam B
authors.initials: MB
authors.lastname: Smeets
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: Laboratory for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology UMC Utrecht, University Medical Center Utrecht, Heidelberglaan 100, Room G02.523, Utrecht 3584 CX, The Netherlands Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands Surgery NUS and Cardiovascular Research Institute, NUHS, Singapore surdvp@nus.edu.sg.
authors.forename: Dominique P V
authors.initials: DP
authors.lastname: De Kleijn
mesh_terms: D000818:Animals; D015936:Complement C5a / Q000378:metabolism; D004195:Disease Models, Animal; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency / Q000378:metabolism*
chemical_list: D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a
keywords: C5a receptor; Infarct size; Ischemia-reperfusion; Leucocyte; Myocardial infarction