Angiotensin-converting enzyme 2 decreases formation and severity of angiotensin II-induced abdominal aortic aneurysms.

ABSTRACT: Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (AngII) to form angiotensin-(1-7) (Ang-(1-7)), which generally opposes effects of AngII. AngII infusion into hypercholesterolemic male mice induces formation of abdominal aortic aneurysms (AAAs). This study tests the hypothesis that deficiency of ACE2 promotes AngII-induced AAAs, whereas ACE2 activation suppresses aneurysm formation.ACE2 protein was detectable by immunostaining in mice and human AAAs. Whole-body deficiency of ACE2 significantly increased aortic lumen diameters and external diameters of suprarenal aortas from AngII-infused mice. Conversely, ACE2 deficiency in bone marrow-derived cells had no effect on AngII-induced AAAs. In contrast to AngII-induced AAAs, ACE2 deficiency had no significant effect on external aortic diameters of elastase-induced AAAs. Because ACE2 deficiency promoted AAA formation in AngII-infused mice, we determined whether ACE2 activation suppressed AAAs. ACE2 activation by administration of diminazene aceturate (30 mg/kg per day) to Ldlr(-/-) mice increased kidney ACE2 mRNA abundance and activity and elevated plasma Ang-(1-7) concentrations. Unexpectedly, administration of diminazene aceturate significantly reduced total sera cholesterol and very low-density lipoprotein-cholesterol concentrations. Notably, diminazene aceturate significantly decreased aortic lumen diameters and aortic external diameters of AngII-infused mice resulting in a marked reduction in AAA incidence (from 73% to 29%). None of these effects of diminazene aceturate were observed in the Ace2(-/y) mice.These results demonstrate that ACE2 exerts a modulatory role in AngII-induced AAA formation, and that therapeutic stimulation of ACE2 could be a benefit to reduce AAA expansion and rupture in patients with an activated renin-angiotensin system.

SUBMITTER: Thatcher SE 

PROVIDER: S-EPMC4250973 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature