Complement anaphylatoxin C4a inhibits C5a-induced neointima formation following arterial injury

Zhao,Yan; Xu,Heng; Yu,Wenhui; Xie,Bao-Dong

doi:10.3892/mmr.2014.2176

Complement anaphylatoxin C4a inhibits C5a-induced neointima formation following arterial injury

Authors:
- Yan Zhao
- Heng Xu
- Wenhui Yu
- Bao-Dong Xie
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Affiliations: Department of Emergency, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China, Department of Vascular Surgery, Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150086, P.R. China, Department of Peripheral Vascular Surgery, The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150001, P.R. China, Department of Cardiovascular Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
Published online on: April 24, 2014 https://doi.org/10.3892/mmr.2014.2176
Pages: 45-52
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Interactions between complement anaphylatoxins have been investigated in numerous fields; however, their functions during arterial remodeling following injury have not been studied. The inhibitory effect of complement anaphylatoxin C4a on neointima formation induced by C5a following arterial injury was investigated. Mice were subjected to wire-induced endothelial denudation of the femoral artery and treated with C5a alone or C5a + C4a for two weeks. C4a significantly inhibited C5a-induced neointima formation and the expression of CD68, F4/80, tumor necrosis factor-α (TNF‑α), interleukin-6 (IL-6) and monocyte chemotactic protein-1 (MCP-1). In vitro, although C4a did not directly inhibit the migration, proliferation or the expression of vascular cell adhesion molecule-1 (VCAM-1) of C5a-induced vascular smooth muscle cells (VSMCs), C5a-pretreated conditioned medium‑induced migration, proliferation and VCAM-1 expression of VSMCs were suppressed when VSMCs were exposed to conditioned medium from C4a-pretreated macrophages. In addition, C5a-induced TNF-α, IL-6 and MCP-1 expression, Ca2+ influx and extracellular signal-regulated kinase (ERK) activation in macrophages were suppressed by C4a. C4a inhibits C5a-induced neointima formation, not by acting directly on VSMCs, but via a macrophage-mediated reaction by inhibiting the Ca2+-dependent ERK pathway in macrophages.

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