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

doi:10.1160/TH14-12-1075

Thrombosis and Haemostasis, Inhaltsverzeichnis

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

¹Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany

,

Yaw Asare

¹Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany

²Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany

,

Janine Köhncke

¹Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany

,

Setareh Alampour-Rajabi

¹Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany

,

Gansuvd Shagdarsuren

³Department of Internal Medicine, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia

,

Andreas Klos

⁴Department for Medical Microbiology, Hannover Medical School, Germany

,

Christian Weber

⁵Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Germany

⁶Department of Medical Biochemistry, Amsterdam Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands

,

Joachim Jankowski

¹Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany

,

Erdenechimeg Shagdarsuren

¹Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen, Germany

› Institutsangaben

Abstract

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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Referenzen

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