Angiotensin-Converting Enzyme 2 Decreases Formation and Severity of Angiotensin II-Induced Abdominal Aortic Aneurysms

作者：Thatcher Sean E; Zhang Xuan; Howatt Deborah A; Yiannikouris Frederique; Gurley Susan B; Ennis Terri; Curci John A; Daugherty Alan; Cassis Lisa A^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2014, 34(12): 2617-2623.

DOI：10.1161/ATVBAHA.114.304613

• angiotensin II
• angiotensin converting enzyme 2
• aortic aneurysms
• abdominal
• hypercholesterolemia

Objective-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. %26lt;br%26gt;Approach and Results-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. %26lt;br%26gt;Conclusions-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.

• 出版日期2014-12