BACKGROUND AND PURPOSEVascular inflammation is a major factor contributing to the development of vascular diseases. The aim of this study was to investigate the role of the nicotinic acetylcholine receptor α3 subtype (α3-nAChR) in vascular inflammation.
EXPERIMENTAL APPROACHVascular inflammation was studied in apolipoprotein E knockout (ApoE À/À ) mice fed a high-fat diet. Inflammatory markers were measured in mouse aortic endothelial cells (MAECs) and macrophages after α3-nAChRs were antagonized pharmacologically, or after the gene of α3-nAChRs was silenced.
KEY RESULTSTreatment with α-conotoxin MII (MII; an α3-nAChR antagonist) increased the number of inflammatory cells infiltrating the aortic walls and further impaired the endothelium-dependent vasodilatations in the aorta of ApoE À/À mice. MII also increased the plasma levels of inflammatory cytokines. Furthermore, the infiltration of classical activated macrophages into the arterial wall of ApoE À/À mice was markedly elevated by MII but that of alternative activated macrophages was reduced. In MAECs, the lipopolysaccharide-stimulated secretion of adhesion molecules and inflammatory cytokines was enhanced by MII, or by silencing the gene of α3-nAChRs. This effect was reversed by inhibitors of the PI3K-Akt-IκKα/β-IκBα-NFκB pathways. In macrophages, the classical activation was enhanced, but the alternative activation was reduced when the gene of α3-nACh receptors was silenced. These effects were prevented by inhibitors of the IκKα/β-IκBα-NFκB and JAK2-STAT6-PPARγ pathways respectively.
CONCLUSIONS AND IMPLICATIONSα3-nAChRs play a pivotal role in regulating the inflammatory responses in endothelial cells and macrophages. The mechanisms involve the modulations of multiple cell signalling pathways.
AbbreviationsApoE, apolipoprotein E; CRP, C reactive protein; ECs, endothelial cells; HE, hematoxylin and eosin; HFD, High-fat Diet; ICAM-1, intercellular adhesion molecule 1; iNOS, inducible NOS; MAECs, mouse aortic endothelial cells; MCP-1, monocyte chemotactic protein 1; MII, α-conotoxin MII; nAChRs, Nicotinic acetylcholine receptors; NO, nitric oxide; PECAM-1, platelet/endothelial cell adhesion molecule 1; PIA, α-Conotoxin PIA; RgIA, α-conotoxin RgIA; siRNAs, Small interfering RNAs; sICAM-1, soluble intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule 1
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