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(Hypertension. 2006;47:718.)
© 2006 American Heart Association, Inc.

Original Articles

Deletion of Angiotensin-Converting Enzyme 2 Accelerates Pressure Overload-Induced Cardiac Dysfunction by Increasing Local Angiotensin II

Koichi Yamamoto; Mitsuru Ohishi; Tomohiro Katsuya; Norihisa Ito; Masashi Ikushima; Masaharu Kaibe; Yuji Tatara; Atsushi Shiota; Sumio Sugano; Satoshi Takeda; Hiromi Rakugi; Toshio Ogihara

From the Department of Geriatric Medicine (T.K., N.I., M.I., M.K., Y.T., A.S., H.R., T.O.), Osaka University Graduate School of Medicine, Suita; Institute of Medical Science (S.S.), University of Tokyo; and the Otsuka GEN Research Institute (S.T.), Otsuka Pharmaceutical Co. Ltd, Tokushima, Japan.

Correspondence to Hiromi Rakugi, Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan. E-mail rakugi{at}geriat.med.osaka-u.ac.jp

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.

Key Words: hypertrophy • remodeling • angiotensin antagonist • receptors, angiotensin

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