{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:40:21Z","timestamp":1791909621849,"version":"4.3.4"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2010,8,17]]},"abstract":"<jats:p><jats:bold><jats:italic>Background\u2014<\/jats:italic><\/jats:bold>Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)\u2013mediated signaling and its adverse effects on the cardiovascular system.<\/jats:p><jats:p><jats:bold><jats:italic>Methods and Results\u2014<\/jats:italic><\/jats:bold>Ang II infusion (1.5 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup>\u00b7 d<jats:sup>\u22121<\/jats:sup>) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (<jats:italic>Ace2<jats:sup>\u2212\/y<\/jats:sup><\/jats:italic>) mice compared with wild-type (WT) mice. Daily treatment of Ang II\u2013infused wild-type mice with recombinant human ACE2 (rhACE2; 2 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup>\u00b7 d<jats:sup>\u22121<\/jats:sup>IP) blunted the hypertrophic response and expression of hypertrophy markers and reduced Ang II\u2013induced superoxide production. Ang II\u2013mediated myocardial fibrosis and expression of procollagen type I\u03b11, procollagen type III\u03b11, transforming growth factor-\u03b21, and fibronectin were also suppressed by rhACE2. Ang II\u2013induced diastolic dysfunction was inhibited by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1-7 levels. rhACE2 treatment inhibited Ang II\u2013mediated activation of protein kinase C-\u03b1 and protein kinase C-\u03b21 protein levels and phosphorylation of the extracellular signal-regulated 1\/2, Janus kinase 2, and signal transducer and activator of transcription 3 signaling pathways in wild-type mice. A subpressor dose of Ang II (0.15 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup>\u00b7 d<jats:sup>\u22121<\/jats:sup>) resulted in a milder phenotype that was strikingly attenuated by rhACE2 (2 mg \u00b7 kg<jats:sup>\u22121<\/jats:sup>\u00b7 d<jats:sup>\u22121<\/jats:sup>IP). In adult ventricular cardiomyocytes and cardiofibroblasts, Ang II\u2013mediated superoxide generation, collagen production, and extracellular signal-regulated 1\/2 signaling were inhibited by rhACE2 in an Ang 1-7\u2013dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wild-type mice.<\/jats:p><jats:p><jats:bold><jats:italic>Conclusions\u2014<\/jats:italic><\/jats:bold>Elevated Ang II induced hypertension, myocardial hypertrophy, fibrosis, and diastolic dysfunction, which were exacerbated by ACE2 deficiency, whereas rhACE2 attenuated Ang II\u2013 and pressure-overload\u2013induced adverse myocardial remodeling. Hence, ACE2 is an important negative regulator of Ang II\u2013induced heart disease and suppresses adverse myocardial remodeling.<\/jats:p>","DOI":"10.1161\/circulationaha.110.955369","type":"journal-article","created":{"date-parts":[[2010,8,3]],"date-time":"2010-08-03T02:59:56Z","timestamp":1280804396000},"page":"717-728","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":394,"title":["Angiotensin-Converting Enzyme 2 Suppresses Pathological Hypertrophy, Myocardial Fibrosis, and Cardiac Dysfunction"],"prefix":"10.1161","volume":"122","author":[{"given":"JiuChang","family":"Zhong","sequence":"first","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ratnadeep","family":"Basu","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Guo","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fung L.","family":"Chow","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Byrns","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Schuster","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Loibner","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu-hua","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josef M.","family":"Penninger","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zamaneh","family":"Kassiri","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin Y.","family":"Oudit","sequence":"additional","affiliation":[{"name":"From the Division of Cardiology (J.C.Z., D.G., F.L.C., S.B., G.Y.O.), Department of Medicine (J.C.Z., R.B., D.G., F.L.C., S.B., Z.K., G.Y.O.) Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada; Department of Physiology (R.B., X.-h.W., Z.K.), University of Alberta, Edmonton, Canada; Apeiron Biologics (M.S., H.L.), Vienna, Austria; and Institute of Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.83.6.1828192"},{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0031-6997(24)01434-0","volume":"52","year":"2000","unstructured":"Kim S, Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. 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