(Hypertension. 2001;37:1394.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Apoptosis Is Not Increased in Myocardium Overexpressing Type 2 Angiotensin II Receptor in Transgenic Mice
From the First Department of Internal Medicine (H.S., S.K., H. Matsuura), Department of Clinical Laboratory Medicine (R.O., M.I., T.B., M.K.), and Second Department of Physiology (Y.T.), Hiroshima University Faculty of Medicine, Hiroshima, Japan; and Internal Medicine II (H. Masaki, H. Matsubara), Kansai Medical University, Osaka, Japan.
Correspondence to Hiroshi Sugino, First Department of Internal Medicine, Hiroshima University Faculty of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan 734-8551. E-mail Hiroshi.Sugino{at}ma7.seikyou.ne.jp
Abstract—To
determine whether angiotensin type 2
(AT2) receptor stimulation induces
apoptosis in cardiomyocytes in vivo, we developed
transgenic mice overexpressing the AT2 receptor
in a cardiac-specific manner, using the 
-myosin heavy-chain
promoter. Ten- to 12-week-old male homozygous transgenic mice (n=44)
and wild-type mice (n=44) were used. Both transgenic and wild-type mice
were given either saline (control), a subpressor dose of
angiotensin II (100 ng ·
kg-1 ·
min-1), a pressor dose of
angiotensin II (1000 ng ·
kg-1 ·
min-1) for 14 days, a pressor dose of
angiotensin II for 28 days to investigate the effects of
stimulation on both angiotensin type 1
(AT1) and AT2 receptors,
the AT1 antagonist L158809 alone, or
a combination of angiotensin II (1000 ng ·
kg-1 ·
min-1) and L158809 for 14 days to
investigate the effects of selective AT2
receptor stimulation. Apoptosis was analyzed in
paraffin-embedded ventricular sections by the terminal
deoxynucleotidyl-transferase–mediated dUTP
nick-end labeling (TUNEL) technique. In both transgenic and wild-type
mice, administration of a subpressor dose of angiotensin
II, L158809, or a combination of angiotensin II and L158809
did not significantly affect the tail-cuff blood pressure or
heart-to-body weight ratio, whereas administration of a pressor dose of
angiotensin II for 14 or 28 days significantly increased
blood pressure and the heart-to-body weight ratio. However, there was
no statistical difference between the effects of
angiotensin II in transgenic and wild-type mice. The number
of TUNEL-positive nuclei was 
0 to 10 per 100 000
cardiomyocytes, with no difference between transgenic and
wild-type mice, regardless of saline infusion or any stimulation. In
infarcted canine myocardial tissue sections for positive control, the
number of TUNEL-positive nuclei was increased by 13.8 to 19.1 times
compared with those in the noninfarcted myocardium. In
conclusion, angiotensin II infusion for a period of 28 days
failed to induce cardiomyocyte apoptosis regardless
of the presence or absence of cardiac AT2
receptor overexpression. It is unlikely that in mice the
AT2 receptor is a strong signal to induce
cardiomyocyte apoptosis in vivo.
Key Words: myocytes, cardiac • apoptosis • mice, transgenic • angiotensin II • L158809
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