From the Vascular Pathophysiology Unit, School of Medicine, University of
Navarra, Pamplona (M.A.F., S.R., J.C.E., J.D.), and the Department of
Medicine, School of Medicine, University of Zaragoza, Zaragoza (J.D.), Spain.
Abstract—An association of increased
apoptosis with overactivity of the local
angiotensin-converting enzyme has been reported in cells
from the left ventricle of adult rats with spontaneous hypertension
(SHR). To gain insight into the regulation of cardiac apoptosis
in arterial hypertension, we investigated the expression of
the proteins Bcl-2 (an inhibitor of apoptosis) and
Bax (an inducer of apoptosis) in the left ventricle of
30-week-old normotensive Wistar-Kyoto rats (WKY), SHR, and SHR treated
with the angiotensin II type 1 receptor (AT1)
antagonist losartan (20 mg ·
kg-1 · d-1) during 14 weeks before
death. The density of apoptotic cells was assessed by direct
immunoperoxidase detection of biotin-labeled deoxyuridin
nucleotides. The expression of Bcl-2 and Bax was assessed
by Western blot analysis. Compared with WKY, untreated SHR
exhibited increased (P<0.05) apoptosis,
increased (P<0.01) Bax, and similar Bcl-2. The
Bcl-2/Bax ratio (an inverse index of cell susceptibility to
apoptosis) was lower (P<0.05) in untreated SHR
than in WKY. The chronic administration of losartan was
associated with the normalization of apoptosis, Bax expression,
and the Bcl-2/Bax ratio in treated SHR. No changes in the expression of
Bcl-2 were observed in these rats after treatment. No significant
changes in the apoptotic density were observed between treated
SHR with normal blood pressure and treated SHR with abnormally high
blood pressure at the end of the treatment period. These results
suggest that an association exists between increased apoptosis
and overexpression of Bax oncoprotein in cells from the left ventricle
of adult SHR. Chronic blockade of AT1 receptors prevents
Bax overexpression and normalizes apoptosis in the left
ventricle of SHR independently of its hemodynamic
effect. On the basis of our findings, it can be proposed that the
interaction of angiotensin II with its AT1
receptors may participate in the stimulation of Bax protein, which in
turn renders cells from the left ventricle of SHR more susceptible
to apoptosis.
© 1998 American Heart Association, Inc.
Scientific Contributions
Overexpression of Bax Protein and Enhanced Apoptosis in the Left Ventricle of Spontaneously Hypertensive Rats
Effects of AT1 Blockade With Losartan
Key Words: angiotensin II • apoptosis • Bax • Bcl-2 • losartan • rats, inbred SHR
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