Atheroprotective role of C5ar2 deficiency in apolipoprotein E-deficient mice

Thromb Haemost. 2015 Oct;114(4):848-58. doi: 10.1160/TH14-12-1075. Epub 2015 Jun 18.


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.

Keywords: Atherosclerosis; complement receptors; cytokines; gene knock-out; vascular remodelling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Apolipoproteins E / deficiency*
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • CD3 Complex / metabolism
  • Carotid Artery Injuries / genetics
  • Carotid Artery Injuries / metabolism
  • Carotid Artery Injuries / pathology
  • Carotid Artery Injuries / prevention & control*
  • Carotid Artery, Common / metabolism
  • Carotid Artery, Common / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Inflammation Mediators / metabolism
  • Macrophages / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neointima
  • Phenotype
  • Plaque, Atherosclerotic
  • Receptor, Anaphylatoxin C5a / deficiency*
  • Receptor, Anaphylatoxin C5a / genetics
  • Receptor, Anaphylatoxin C5a / metabolism
  • Rupture, Spontaneous
  • T-Lymphocytes / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Cell Adhesion Molecule-1 / genetics
  • Vascular Cell Adhesion Molecule-1 / metabolism
  • Vascular Remodeling


  • Apolipoproteins E
  • C5ar1 protein, mouse
  • C5ar2 protein, mouse
  • CD3 Complex
  • Inflammation Mediators
  • Receptor, Anaphylatoxin C5a
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1