title: Stimulation of α7 nicotinic acetylcholine receptor by AR-R17779 suppresses atherosclerosis and aortic aneurysm formation in apolipoprotein E-deficient mice.
abstract: Atherosclerosis is a chronic inflammatory disease. It has been appreciated that vagus nerve inhibits macrophage activation via α7 nicotinic acetylcholine receptor (nAChR), termed the cholinergic anti-inflammatory pathway. We explored the effects of AR-R17779, a selective α7nAChR agonist, on atherosclerosis and aneurysm formation in apolipoprotein E (ApoE)-deficient mice. ApoE-deficient mice were fed a high-fat diet (HFD) and angiotensin II (Ang II) was infused by osmotic minipumps from 10-week-old for 4weeks. AR-R17779 was given in drinking water ad libitum. Oil red O staining of the aorta showed that combined loading of HFD and Ang II induced marked atherosclerosis compared with control mice fed a normal chow. Treatment with AR-R17779 significantly reduced atherosclerotic plaque area and improved survival of mice. Treatment with AR-R17779 also suppressed abdominal aortic aneurysm formation. Quantitative RT-PCR of the aorta revealed that mRNA expression levels of interleukin-1β, interleukin-6 and NOX2 were significantly decreased in AR-R17779-treated mice compared with Ang II+HFD mice. AR-R17779 treatment also reduced blood pressure and serum lipid levels. In conclusion, α7nAChR activation attenuates atherogenesis and aortic abdominal aneurysm formation in ApoE-deficient mice possibly through an anti-inflammatory effect and reduction of blood pressure and lipid levels. Pharmacological activation of α7nAChR may have a therapeutic potential against atherosclerotic vascular diseases through multiple mechanisms.
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. Electronic address: ichiki@cardiol.med.kyushu-u.ac.jp.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ichiki
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Strategy Team, CVMD IMED, AstraZeneca, Mölndal, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hurt-Camejo
authors.affiliation: Department of Bioscience, CVMD IMED, AstraZeneca, Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Michaëlsson
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Ikeda
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Inoue
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Matsuura
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Tomotake
authors.initials: T
authors.lastname: Tokunou
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Kitamoto
authors.affiliation: Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001014:Aortic Aneurysm / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000517:prevention & control*; D001794:Blood Pressure / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism
chemical_list: C408128:AR-R 17779; D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D001952:Bridged-Ring Compounds; D008055:Lipids; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Angiotensin receptor; Atherosclerosis; Cholinergic anti-inflammatory pathway; Inflammation; α7-Nicotinic acetylcholine receptor