title: Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II.
abstract: Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2(-/y) mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2(-/y) mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2(-/y) mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2(-/y) mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2(-/y) mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2(-/y) mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2(-/y) mice in response to TAC. Administration of candesartan, an AT1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2(-/y) mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2(-/y) mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.
authors.affiliation: Department of Geriatric Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohishi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Norihisa
authors.initials: N
authors.lastname: Ito
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikushima
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kaibe
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tatara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiota
authors.forename: Sumio
authors.initials: S
authors.lastname: Sugano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takeda
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D000804:Angiotensin II / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001011:Aorta; D002268:Carboxypeptidases / Q000235:genetics* / Q000378:metabolism; D002303:Cardiac Output, Low / Q000209:etiology / Q000235:genetics; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D004789:Enzyme Activation / Q000187:drug effects; D017353:Gene Deletion; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000201:enzymology; D009994:Osmolar Concentration; D007703:Peptidyl-Dipeptidase A; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases; D002268:Carboxypeptidases; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2