Cui Yang1,2, Zhengtao Li3, Saimei Yan3, Yonghui He3, Rong Dai4, George Pek-Heng Leung5, Shitian Pan3, Jinyan Yang3, Rong Yan6, Guanhua Du7. 1. Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650500, China. yangynni@163.com. 2. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. yangynni@163.com. 3. Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan Minzu University, Kunming, 650500, China. 4. Department of Pharmacology, Yunnan University of TCM, Kunming, 650500, China. 5. Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China. 6. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. 7. State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. dugh@imm.ac.cn.
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 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.
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.
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