title: Atheroprotective role of C5ar2 deficiency in apolipoprotein E-deficient mice.
abstract: Atherogenic processes and vascular remodelling after arterial injury are controlled and driven by a plethora of factors amongst which the activation of the complement system is pivotal. Recently, we reported a clear correlation between high expressions of the second receptor for complement anaphylatoxin C5a, the C5a receptor-like 2 (C5L2, C5aR2), with high pro-inflammatory cytokine expression in advanced human atherosclerotic plaques. This prompted us to speculate that C5aR2 might have a functional role in atherosclerosis. We, therefore, investigated the role of C5aR2 in atherosclerosis and vascular remodelling. Here, we demonstrate that C5ar2 deletion, in atherosclerosis-prone mice, attenuates atherosclerotic as well as neointimal plaque formation, reduces macrophages and CD3+ T cells and induces features of plaque stability, as analysed by histomorphometry and quantitative immunohistochemistry. As a possible underlying mechanism, C5ar2-deficient plaques showed significantly reduced expression of C5a receptor (C5ar1), Tnf-α as well as Vcam-1, as determined by qPCR and quantitative immunohistochemistry. In addition, in vitro mechanistic studies revealed a reduction of these pro-inflammatory and pro-atherosclerotic mediators in C5ar2-deficient macrophages. Finally, blocking C5ar1 with antagonist JPE1375, in C5ar2(-/-)/Apoe(-/-) mice, led to a further reduction in neointimal plaque formation with reduced inflammation. In conclusion, C5ar2 deficiency attenuates atherosclerosis and neointimal plaque formation after arterial injury. This identifies C5aR2 as a promising target to reduce atherosclerosis and restenosis after vascular interventions.
authors.forename: Jaco
authors.initials: J
authors.lastname: Selle
authors.forename: Yaw
authors.initials: Y
authors.lastname: Asare
authors.forename: Janine
authors.initials: J
authors.lastname: Köhncke
authors.forename: Setareh
authors.initials: S
authors.lastname: Alampour-Rajabi
authors.forename: Gansuvd
authors.initials: G
authors.lastname: Shagdarsuren
authors.forename: Andreas
authors.initials: A
authors.lastname: Klos
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Joachim
authors.initials: J
authors.lastname: Jankowski
authors.affiliation: Erdenechimeg Shagdarsuren, MD, Institute for Molecular Cardiovascular Research, Universitätsklinikum der RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany, Tel.: +49 241 8036584, Fax: +49 241 8082703, E-mail: eguenther@ukaachen.de.
authors.forename: Erdenechimeg
authors.initials: E
authors.lastname: Shagdarsuren
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017252:CD3 Complex / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058426:Neointima; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012422:Rupture, Spontaneous; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: D001057:Apolipoproteins E; C000591759:C5ar1 protein, mouse; C000594938:C5ar2 protein, mouse; D017252:CD3 Complex; D018836:Inflammation Mediators; D044087:Receptor, Anaphylatoxin C5a; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1
keywords: Atherosclerosis; complement receptors; cytokines; gene knock-out; vascular remodelling