title: Azelnidipine suppresses the progression of aortic aneurysm in wild mice model through anti-inflammatory effects.
abstract: BACKGROUND
  Although systemic hypertension is closely associated with aortic aneurysm (AA) formation, there are many patients with AA without hypertension. In these patients, an inflammation-mediated progression of aneurysmal disease is likely responsible for AA growth and eventual rupture. Unfortunately, there remains no reproducible and durable small animal model of aortic aneurysmal disease, the development of which would enable the investigation of the pathophysiology of this vexing condition. The first aim was to establish a useful wild-type mouse model of AA with low mortality. The second aim was to use this model to assess the protective effect of azelnidipine, a new calcium channel blocker, against the progression of the AA independent of its antihypertensive effect.
  
  
  METHODS
  Angiotensin II and β-aminopropionitrile (a lysyl oxidase inhibitor) were administrated subcutaneously in 7-week-old C57BL/6J mice using an osmotic minipump for 4 weeks to generate a wild-type mouse model of AA. Concurrently, azelnidipine (a calcium channel blocker) or a placebo was administrated orally for 4 weeks. Mice were humanely killed and assessed at the end of the 4 weeks of pharmacologic manipulation.
  
  
  RESULTS
  The combined infusion of angiotensin II and β-aminopropionitrile induced degenerative aneurysm of the thoracic and/or abdominal aorta (11/12; 92%). The majority of aneurysms were located in the distal aortic arch and suprarenal abdominal aorta. Although there was no difference in systolic blood pressure between the control and azelnidipine-treated groups, azelnidipine significantly reduced the incidence of AA (2/11; 18%). Azelnidipine treatment reduced the pathologic findings normally associated with aneurysm formation within the aortic wall. Azelnidipine also reduced the number of macrophage antigen-3 (MAC-3)-positive cells in the periaortic adipose tissue and reduced the gene expression levels of tumor necrosis factor-alpha and matrix metalloproteinase-2 and -9 within the aortic wall.
  
  
  CONCLUSIONS
  This study demonstrates that combined treatment with angiotensin II and β-aminopropionitrile induces degenerative AAs in wild-type mice, and azelnidipine prevents aneurysm progression via its anti-inflammatory effect.
authors.affiliation: Department of Cardiovascular Surgery, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan; Department of Surgery, Yale University School of Medicine, New Haven, Conn. Electronic address: hirotsugu.kurobe@clin.med.tokushima-u.ac.jp.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Kurobe
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Noriko
authors.initials: N
authors.lastname: Sugasawa
authors.forename: Mark W
authors.initials: MW
authors.lastname: Maxfield
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kitagawa
mesh_terms: D000629:Aminopropionitrile; D000804:Angiotensin II; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017545:Aortic Aneurysm, Thoracic / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001383:Azetidinecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D056564:Sirtuin 1 / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D000629:Aminopropionitrile; D001383:Azetidinecarboxylic Acid; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C061679:azelnidipine
keywords: 16; 26.1; 29; AA; BAPN; EVG; H&E; MMP; RT-PCR; TNF-α; aortic aneurysm; elastica van Gieson; hematoxylin and eosin; matrix metalloproteinase; reverse-transcriptase polymerase chain reaction; tumor necrosis factor-alpha; β-aminopropionitrile