title: Complement C5a inhibition reduces atherosclerosis in ApoE-/- mice.
abstract: The complement C5a receptor, CD88, is present on many of the cells found within human atherosclerotic plaques, but little is known about the role of C5a in atherogenesis. Using real-time PCR, we determined that ApoE(-/-) mice fed a normal diet express more aortic CD88 mRNA compared with controls, and this increase coincides with atherosclerotic lesion development (P<0.001 for 3- vs. 25-wk-old animals). Conversely, mRNA expression of the alternative C5a receptor, C5L2, in aortas of ApoE(-/-) mice, was lower than controls at all time points. Using immunohistochemistry, we confirmed the presence of CD88 on macrophages, smooth muscle cells, and activated endothelial cells in plaques from brachiocephalic arteries. Treatment of ApoE(-/-) mice with a CD88 antagonist (PMX53; 3 mg/kg s.c. 3 ×/wk plus 1 mg/kg/d p.o.) for 25 wk reduced lesion size and lipid content in the plaque by ∼ 40% (P<0.05). Our study provides evidence for a proatherogenic role for C5a and identifies the CD88 antagonist PMX53 as a potential antiatherosclerotic drug.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia. helga.manthey@uni-wuerzburg.de
authors.forename: Helga D
authors.initials: HD
authors.lastname: Manthey
authors.forename: Anita C
authors.initials: AC
authors.lastname: Thomas
authors.forename: Ian A
authors.initials: IA
authors.lastname: Shiels
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolfe
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D016122:Brachiocephalic Trunk / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D008055:Lipids / Q000032:analysis / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D001057:Apolipoproteins E; C000594938:C5ar2 protein, mouse; D008055:Lipids; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D015936:Complement C5a; D002784:Cholesterol