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

Abstract

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, while ACE2 activation suppresses aneurysm formation. 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. Since ACE2 deficiency promoted AAA formation in AngII-infused mice, we determined if ACE2 activation suppressed AAAs. ACE2 activation by administration of diminazine aceturate (DIZE, 30 mg/kg/day) to Ldlr−/− mice increased kidney ACE2 mRNA abundance and activity and elevated plasma Ang-(1-7) concentrations. Unexpectedly, administration of DIZE significantly reduced total sera cholesterol and VLDL-cholesterol concentrations. Notably, DIZE 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 DIZE were observed in the Ace2−/y mice. 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.

Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II/β-Aminopropionitrile–Induced Abdominal Aortic Aneurysm

“…Other ADAM17 substrates including TNFα, Notch1 and angiotensin converting enzyme 2 may also participate in AAA pathology according to literature 17, 24, 25 . Note that while the protein expression analysis of TNFα did not show any enhancement in AAA, the experiment did not measure the potential conversion of pro-TNFα to mature and active TNFα by ADAM17.…”

Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice

“…Diminazene actions on the cardiovascular system have been documented in different conditions. For instance, diminazene attenuates pulmonary hypertension [27], reduces damages in cardiac [41] and stroke ischemia [42], improves erectile function [43], as well as other beneficial effects [44,45]. …”

An update on the etiology of abdominal aortic aneurysms: implications for future diagnostic testing

“…The apolipoprotein E (apoE) and low-density lipoprotein receptor (LDLR)-deficient mice were a step closer to a molecular model of AAA [81,82]. Both the apoE À/À and the LDLR À/À mice develop aneurysms and atherosclerotic lesions throughout the length of the aorta if fed high cholesterol diets [82,83]. Although the apoE-deficient mouse has limited applicability to humans, both the apoE-deficient mice and the LDLR-deficient mice highlight the role of lipid metabolism in the development of AAA [84].…”