PMID- 27572927 OWN - NLM STAT- MEDLINE DCOM- 20171030 LR - 20210109 IS - 1476-5381 (Electronic) IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 173 IP - 22 DP - 2016 Nov TI - Role of the nicotinic acetylcholine receptor alpha3 subtype in vascular inflammation. PG - 3235-3247 LID - 10.1111/bph.13609 [doi] AB - 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 alpha3 subtype (alpha3-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 alpha3-nAChRs were antagonized pharmacologically, or after the gene of alpha3-nAChRs was silenced. KEY RESULTS: Treatment with alpha-conotoxin MII (MII; an alpha3-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 alpha3-nAChRs. This effect was reversed by inhibitors of the PI3K-Akt-IkappaKalpha/beta-IkappaBalpha-NFkappaB pathways. In macrophages, the classical activation was enhanced, but the alternative activation was reduced when the gene of alpha3-nACh receptors was silenced. These effects were prevented by inhibitors of the IkappaKalpha/beta-IkappaBalpha-NFkappaB and JAK2-STAT6-PPARgamma pathways respectively. CONCLUSIONS AND IMPLICATIONS: alpha3-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. CI - (c) 2016 The British Pharmacological Society. FAU - Yang, Cui AU - Yang C AD - 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. AD - 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. FAU - Li, Zhengtao AU - Li Z AD - 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. FAU - Yan, Saimei AU - Yan S AD - 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. FAU - He, Yonghui AU - He Y AD - 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. FAU - Dai, Rong AU - Dai R AD - Department of Pharmacology, Yunnan University of TCM, Kunming, 650500, China. FAU - Leung, George Pek-Heng AU - Leung GP AD - Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong, China. FAU - Pan, Shitian AU - Pan S AD - 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. FAU - Yang, Jinyan AU - Yang J AD - 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. FAU - Yan, Rong AU - Yan R AD - 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. FAU - Du, Guanhua AU - Du G AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160929 PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Apolipoproteins E) RN - 0 (Conotoxins) RN - 0 (Nicotinic Antagonists) RN - 0 (Receptors, Nicotinic) RN - 0 (alpha-conotoxin MII) RN - 0 (nicotinic receptor subunit alpha3) SB - IM MH - Animals MH - Apolipoproteins E/deficiency/metabolism MH - Conotoxins/administration & dosage/*pharmacology MH - Inflammation/*drug therapy/metabolism MH - Macrophages/drug effects/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Nicotinic Antagonists/administration & dosage/*pharmacology MH - Receptors, Nicotinic/*metabolism MH - Vascular Diseases/*drug therapy/metabolism PMC - PMC5071564 EDAT- 2016/10/21 06:00 MHDA- 2017/10/31 06:00 PMCR- 2017/11/01 CRDT- 2016/08/31 06:00 PHST- 2015/12/18 00:00 [received] PHST- 2016/08/11 00:00 [revised] PHST- 2016/08/19 00:00 [accepted] PHST- 2016/10/21 06:00 [pubmed] PHST- 2017/10/31 06:00 [medline] PHST- 2016/08/31 06:00 [entrez] PHST- 2017/11/01 00:00 [pmc-release] AID - BPH13609 [pii] AID - 10.1111/bph.13609 [doi] PST - ppublish SO - Br J Pharmacol. 2016 Nov;173(22):3235-3247. doi: 10.1111/bph.13609. Epub 2016 Sep 29.