This study was undertaken to elucidate a novel mechanism underlying
angiotensin II-induced cardiac injury, focusing on the role of oxidative stress and myocardial capillary density.
Salt-loaded Dahl
salt-sensitive hypertensive rats (DS rats), a useful model for hypertensive cardiac remodeling or
heart failure, were orally given
irbesartan (an AT1 receptor blocker),
tempol (a
superoxide dismutase mimetic) or
hydralazine (a
vasodilator).
Irbesartan significantly ameliorated left ventricular
ischemia and prevented the development of
cardiac hypertrophy and
fibrosis in DS rats. The benefits were associated with the attenuation of oxidative stress, normalization of myocardial capillary density and inhibition of capillary endothelial apoptosis. Moreover, DS rats with significant
cardiac hypertrophy and
fibrosis displayed decreased myocardial
vascular endothelial growth factor (
VEGF) expression and increased cardiac
apoptosis signal-regulating kinase 1 (ASK1) activation. Treatment with
irbesartan significantly reversed these phenotypes.
Tempol treatment of DS rats mimicked all the above-mentioned effects of
irbesartan, indicating the critical role of oxidative stress in cardiac injury. We also investigated the role of
VEGF and ASK1 in oxidative stress-induced endothelial apoptosis by using cultured endothelial cells from wild-type and ASK1-deficient mice. Oxidative stress-induced ASK1 activation led to endothelial apoptosis, and
VEGF treatment prevented oxidative stress-induced endothelial apoptosis by inhibiting ASK1 activation. We obtained the first evidence that oxidative stress-induced cardiac
VEGF repression and ASK1 activation caused the enhancement of endothelial apoptosis and contributed to a decrease in myocardial capillary density. These effects resulted in
angiotensin II-induced progression of cardiac injury.