title: 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, whereas ACE2 activation suppresses aneurysm formation.
  
  
  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.
  
  
  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.
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: Sean E
authors.initials: SE
authors.lastname: Thatcher
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Howatt
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: Frederique
authors.initials: F
authors.lastname: Yiannikouris
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: Susan B
authors.initials: SB
authors.lastname: Gurley
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: Terri
authors.initials: T
authors.lastname: Ennis
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: John A
authors.initials: JA
authors.lastname: Curci
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.).
authors.forename: Alan
authors.initials: A
authors.lastname: Daugherty
authors.affiliation: From the Department of Pharmacology and Nutritional Sciences (S.E.T., F.Y., L.A.C.), Graduate Center for Toxicology (X.Z.), and Saha Cardiovascular Research Center, Department of Internal Medicine (D.A.H., A.D.), University of Kentucky, Lexington; Division of Nephrology, Department of Medicine, Duke University, Durham, NC (S.B.G.); and Department of Surgery, Section of Vascular Surgery, Washington University, St Louis, MO (T.E., J.A.C.). lcassis@uky.edu.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Cassis
mesh_terms: D000368:Aged; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000150:complications / Q000378:metabolism; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012084:Renin-Angiotensin System
chemical_list: D012333:RNA, Messenger; D011973:Receptors, LDL; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C003915:diminazene aceturate; D004133:Diminazene
keywords: angiotensin II; angiotensin converting enzyme 2; aortic aneurysms, abdominal; hypercholesterolemia