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

Atheroprotective role of C5ar2 deficiency in apolipoprotein E-deficient mice

Jaco Selle, Yaw Asare, Janine Köhncke, Setareh Alampour-Rajabi, Gansuvd Shagdarsuren, Andreas Klos, Christian Weber, Joachim Jankowski, Erdenechimeg Shagdarsuren  1
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Atheroprotective role of C5ar2 deficiency in apolipoprotein E-deficient mice

Jaco Selle et al. Thromb Haemost. 2015 Oct.

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.

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

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