title: Angiotensin-converting enzyme 2 is a critical determinant of angiotensin II-induced loss of vascular smooth muscle cells and adverse vascular remodeling.
abstract: Angiotensin-converting enzyme (ACE) 2 is a key negative regulator of the renin-angiotensin system and metabolizes angiotensin II (Ang II) into Ang 1 to 7. Ang II is a vasoactive peptide, which plays an important role in vascular disease. The objective of the present study was to define the role of ACE2 in pathological vascular remodeling. We found upregulation of ACE2 in dilated human aorta with bicuspid aortic valve and in murine aorta in response to Ang II. Ex vivo pressure myography showed increased vascular stiffness in ACE2 knockout (KO) mesenteric arteries in response to Ang II (1.5 mg/kg per day) and with aging. Histological analyses revealed reduced media-to-lumen ratio in ACE2KO mesenteric arteries with loss of vascular smooth muscle cells. Aortic vascular smooth muscle cells from ACE2KO mice showed markedly increased reactive oxygen species and apoptosis in response to Ang II along with increased cleaved caspase-3 and cleaved caspase-8 levels in the ACE2KO aorta. Ang II type 1 receptor blockade and Ang 1 to 7 supplementation prevented the increase in Ang II-induced reactive oxygen species and apoptotic cell death. In the aorta, Ang II resulted in thoracic and abdominal aortic dilation with loss of vascular smooth muscle cell density in ACE2KO aorta as revealed by α-smooth muscle actin, calponin staining, and electron microscopy with increased promatrix metalloproteinase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 levels. ACE2 is upregulated in vascular diseases, and ACE2 deficiency exacerbates Ang II-mediated vascular remodeling driven by increased reactive oxygen species and vascular smooth muscle cell apoptosis. In conclusion, the key counter-regulatory role of ACE2 against an activated renin-angiotensin system provides novel insights into the role of ACE2 in vascular diseases.
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Vaibhav B
authors.initials: VB
authors.lastname: Patel
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Jiu-Chang
authors.initials: JC
authors.lastname: Zhong
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Dong
authors.initials: D
authors.lastname: Fan
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Ratnadeep
authors.initials: R
authors.lastname: Basu
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Jude S
authors.initials: JS
authors.lastname: Morton
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Nirmal
authors.initials: N
authors.lastname: Parajuli
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Michael Sean
authors.initials: MS
authors.lastname: McMurtry
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.).
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: From the Division of Cardiology, Department of Medicine (V.B.P., N.P., M.S.M., G.Y.O.), Mazankowski Alberta Heart Institute (V.B.P., D.F., R.B., N.P., S.T.D., Z.K., G.Y.O.), Department of Physiology (D.F., R.B., S.T.D., Z.K., G.Y.O.), and Department of Obstetrics and Gynecology (J.S.M., S.T.D.), University of Alberta, Edmonton, Alberta, Canada; State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (J.-C.Z.); and Shanghai Key Laboratory of Hypertension, Shanghai Institute of Hypertension, Shanghai, China (J.-C.Z.). gavin.oudit@ualberta.ca.
authors.forename: Gavin Y
authors.initials: GY
authors.lastname: Oudit
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D059289:Vascular Stiffness / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology*
chemical_list: D017382:Reactive Oxygen Species; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D020782:Matrix Metalloproteinases
keywords: angiotensin II; angiotensin converting enzyme 2; irbesartan