• Ryota Ishibashi, Tomohiro Aoki, Masaki Nishimura, and Susumu Miyamoto.
• Department of Neurosurgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
• Neurosurgery. 2012 Mar 1;70(3):722-30.

BackgroundCerebral 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.ObjectiveTo 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.MethodsSurgically 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.ResultsImidapril 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.ConclusionAngiotensin-converting enzyme is not involved in the pathogenesis of CA formation. Imidapril suppresses CA formation in an ACE-independent and MMP-9-dependent manner.

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