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Thromb Haemost 2015; 114(04): 848-858
DOI: 10.1160/TH14-12-1075
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

Atheroprotective role of C5ar2 deficiency in apolipoprotein E-deficient mice

Jaco Selle
1   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany
,
Yaw Asare
1   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany
2   Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
,
Janine Köhncke
1   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany
,
Setareh Alampour-Rajabi
1   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany
,
Gansuvd Shagdarsuren
3   Department of Internal Medicine, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
,
Andreas Klos
4   Department for Medical Microbiology, Hannover Medical School, Germany
,
Christian Weber
5   Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Germany
6   Department of Medical Biochemistry, Amsterdam Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
,
Joachim Jankowski
1   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany
,
Erdenechimeg Shagdarsuren
1   Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany
› Author Affiliations Financial support: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grant (GU1223/3–1) to E.S.
Further Information

Publication History

Received: 23 December 2014

Accepted after major revision: 20 May 2015

Publication Date:
29 November 2017 (online)

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Summary

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.

The review process for this paper was fully handled by Gregory Y. H. Lip, Editor in Chief.

Keywords

Atherosclerosis - complement receptors - cytokines - vascular remodelling - gene knock-out

 

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