title: Imidapril inhibits cerebral aneurysm formation in an angiotensin-converting enzyme-independent and matrix metalloproteinase-9-dependent manner.
abstract: BACKGROUND
  Cerebral aneurysms (CAs) have a high prevalence in the general population and cause lethal subarachnoid hemorrhage. We recently demonstrated that chronic inflammation is an underlying pathogenesis of CA. However, we identified the negative involvement of angiotensin receptor signaling in the pathogenesis of CA.
  
  
  OBJECTIVE
  To elucidate the involvement of the renin-angiotensin system (RAS) by assessing the expression and activity of angiotensin-converting enzyme (ACE), a key enzyme of RAS, during CA formation and evaluating the effect of imidapril, an ACE inhibitor and a potent inhibitor of matrix metalloproteinase-9 (MMP-9), on CA formation.
  
  
  METHODS
  Surgically induced CA models of rats were used. Imidapril was given intraperitoneally to rats, and aneurysm size and medial thickness of CAs were examined 1 month after induction. Then, ACE and MMP-9 expression was assessed by immunostaining and Western blot analysis. The MMP-9 activity was evaluated by gelatin zymography, and ACE expression in human CA walls was assessed by immunostaining.
  
  
  RESULTS
  Imidapril significantly suppressed the size and medial thinning of induced CAs. The expression and activity of ACE were not induced in CA walls. Furthermore, imidapril treatment did not influence ACE expression and activity, suggesting that the inhibitory effect of imidapril was independent of an inhibition of the RAS. Imidapril inhibited MMP-9 activity upregulated in CA walls. In an in vitro study, imidapril suppressed MMP-9 activity in a dose-dependent manner. In human CA walls, as in the rat model, ACE expression was not upregulated.
  
  
  CONCLUSIONS
  Angiotensin-converting enzyme is not involved in the pathogenesis of CA formation. Imidapril suppresses CA formation in an ACE-independent and MMP-9-dependent manner.
authors.affiliation: Department of Neurosurgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Ishibashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Aoki
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048289:Imidazolidines / Q000494:pharmacology*; D002532:Intracranial Aneurysm / Q000378:metabolism* / Q000517:prevention & control*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012720:Severity of Illness Index; D013345:Subarachnoid Hemorrhage / Q000378:metabolism / Q000517:prevention & control
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D048289:Imidazolidines; D061965:Matrix Metalloproteinase Inhibitors; C065166:imidapril; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat