title: Suppression of abdominal aortic aneurysm formation by AR-R17779, an agonist for the α7 nicotinic acetylcholine receptor.
abstract: OBJECTIVE
  Activation of vagal nerve suppresses inflammatory responses through activation of α7 nicotinic acetylcholine receptor (nAchR). We sought to determine whether AR-R17779, a selective agonist of α7nAchR, affects the development of abdominal aortic aneurysm (AAA).
  
  
  RESULTS
  AAA was induced by topical application of calcium chloride (CaCl2) to abdominal aorta (AAA group). NaCl (0.9%) was substituted for CaCl2 as a sham operation (SHAM group). AR-R17779 was administered in drinking water (AAA/AR-R group). One and 6 weeks after the operation, aortic tissue was excised for histological and molecular analyses. Aortic diameter and macrophage infiltration into the aortic adventitia were increased in AAA group compared with SHAM group at 6 weeks. Treatment with AR-R17779 reduced the diameter of the aorta and macrophage infiltration compared with AAA group. Wavy morphology of the elastic lamellae was lost in AAA group while it was preserved in AAA/AR-R group. Expression of inflammatory cytokines and matrix metalloproteinase (MMP) activities were enhanced in AAA group, which was suppressed in AAA/AR-R group. AR-R17779 treatment suppressed CaCl2-induced expression of cytokines, activities of MMPs and NF-κB activation at 1 week when aortic dilatation had not developed.
  
  
  CONCLUSIONS
  Treatment with AR-R17779 prevented the enlargement of abdominal aorta induced by CaCl2 in association with reduced inflammation and extracellular matrix disruption. These findings suggest therapeutic potential of α7nAchR activation for prevention of AAA development.
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; 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: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kojima
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahara
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: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Chikahiro
authors.initials: C
authors.lastname: Sankoda
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Ikeda
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Inoue
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Tomotake
authors.initials: T
authors.lastname: Tokunou
authors.affiliation: Departments of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; 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: Departments 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; D017544:Aortic Aneurysm, Abdominal / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013141:Spiro Compounds / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: C408128:AR-R 17779; D001952:Bridged-Ring Compounds; D016207:Cytokines; D013141:Spiro Compounds; D064569:alpha7 Nicotinic Acetylcholine Receptor; D012313:RNA; D020782:Matrix Metalloproteinases
keywords: Abdominal aortic aneurysm; Cytokines; Matrix metalloproteinase; α7 nicotinic acetylcholine receptor