Atheroprotective role of C5ar2 deficiency in apolipoprotein E-deficient mice

作者：Selle Jaco; Asare Yaw; Kohncke Janine; Alampour Rajabi Setareh; Shagdarsuren Gansuvd; Klos Andreas; Weber Christian; Jankowski Joachim; Shagdarsuren Erdenechimeg^*

来源：Thrombosis and Haemostasis, 2015, 114(4): 848-858.

DOI：10.1160/TH14-12-1075

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

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 atherosclerosisprone 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-alpha 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 WEI 375, 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.

• 出版日期2015-10