From the Department of Medicine III (K.H., I.K., I.S., D.H., S.K., T.M.,
Y.Y.), University of Tokyo School of Medicine; Second Department of Internal
Medicine (K.K., H.M.), Kansai Medical University, Osaka; Lead Generation
Research Laboratories (T.S.), Tanabe Seiyaku Co, Ltd, Osaka; and Institute of
Applied Biochemistry (K.M.), University of Tsukuba, Ibaraki, Japan.
Correspondence to Issei Komuro, MD, Department of Medicine III, University of Tokyo School of Medicine, 73-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.u-tokyo.ac.jp
BackgroundMany studies have
suggested that the renin-angiotensin system plays an
important role in the development of pressure overloadinduced cardiac
hypertrophy. Moreover, it has been reported that pressure
overloadinduced cardiac hypertrophy is completely
prevented by ACE inhibitors in vivo and that the stored
angiotensin II (Ang II) is released from cardiac myocytes
in response to mechanical stretch and induces cardiomyocyte
hypertrophy through the Ang II type 1 receptor
(AT1) in vitro. These results suggest that the
AT1-mediated signaling is critical for the development of
mechanical stressinduced cardiac hypertrophy.
Methods and ResultsTo determine whether AT1-mediated
signaling is indispensable for the development of pressure
overloadinduced cardiac hypertrophy, pressure overload
was produced by constricting the abdominal aorta of AT1A
knockout (KO) mice. Quantitative reverse transcriptasepolymerase
chain reaction revealed that the cardiac AT1 (probably
AT1B) mRNA levels in AT1A KO mice were <10%
of those of wild-type (WT) mice and were not affected by pressure
overload. Chronic treatment with subpressor doses of Ang II increased
left ventricular mass in WT mice but not in KO mice.
Pressure overload, however, fully induced cardiac
hypertrophy in KO as well as WT mice. There were no
significant differences between WT and KO mice in expression levels of
fetal-type cardiac genes, in the left ventricular wall
thickness and systolic function as revealed by the
transthoracic echocardiogram, or in the
histological changes such as myocyte
hypertrophy and fibrosis.
ConclusionsAT1-mediated Ang II signaling is not
essential for the development of pressure overloadinduced cardiac
hypertrophy.
© 1998 American Heart Association, Inc.
Basic Science Reports
Pressure Overload Induces Cardiac Hypertrophy in Angiotensin II Type 1A Receptor Knockout Mice
Key Words: hypertrophy pressure angiotensin genes
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