Role of the nicotinic acetylcholine receptor α3 subtype in vascular inflammation.

BACKGROUND AND PURPOSE

Vascular 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 APPROACH

Vascular inflammation was studied in apolipoprotein E knockout (ApoE ) 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 RESULTS

Treatment 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 mice. MII also increased the plasma levels of inflammatory cytokines. Furthermore, the infiltration of classical activated macrophages into the arterial wall of ApoE 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 IMPLICATIONS

α3-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.