Role of the nicotinic acetylcholine receptor ?3 subtype in vascular inflammation.

ABSTRACT: 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 ?3 subtype (?3-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 ?3-nAChRs were antagonized pharmacologically, or after the gene of ?3-nAChRs was silenced. KEY RESULTS:Treatment with ?-conotoxin MII (MII; an ?3-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 ?3-nAChRs. This effect was reversed by inhibitors of the PI3K-Akt-I?K?/?-I?B?-NF?B pathways. In macrophages, the classical activation was enhanced, but the alternative activation was reduced when the gene of ?3-nACh receptors was silenced. These effects were prevented by inhibitors of the I?K?/?-I?B?-NF?B and JAK2-STAT6-PPAR? pathways respectively. CONCLUSIONS AND IMPLICATIONS:?3-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.

SUBMITTER: Yang C 

PROVIDER: S-EPMC5071564 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature