The use of beta-blockers has emerged as a beneficial treatment for
cardiac hypertrophy.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in
cardiac hypertrophy due to pressure overload and
after treatment with beta-blocker is little known. To evaluate the effect of
carvedilol on both myocardial HIF-1alpha expression and
cardiac hypertrophy, infra-renal aortic banding was performed for 4 weeks in adult Sprague-Dawley rats to induce
cardiac hypertrophy.
Carvedilol at 50 mg/kg
body weight per day after surgery was given. Heart weight and the ratio of heart weight and
body weight increased significantly after aortic banding for 4 weeks in the absence of
drug treatment. Mean arterial pressure increased from 80 +/- 9 mmHg in the
sham group to 94 +/-5 mmHg (p < 0.001) in the banding group. Echocardiography showed concentric
hypertrophy after aortic banding. Mean arterial pressure decreased
after treatment with
carvedilol. The increased wall thickness and heart weight was reversed to normal by
carvedilol. Western blot showed that HIF-1alpha,
vascular endothelial growth factor (
VEGF) and
brain natriuretic peptide (BNP)
proteins were up-regulated and
nerve growth factor-beta (
NGF-beta) down-regulated in the banding group. Treatment with
valsartan,
doxazosin, or
N-acetylcysteine did not significantly affect HIF-1alpha and
VEGF proteins expression in the banding groups. Real-time polymerase chain reaction showed that
mRNA of HIF-1alpha,
VEGF and BNP increased and
mRNA of
NGF-beta decreased in the banding group. Treatment with
carvedilol reversed both
protein and
mRNA of HIF-1alpha,
VEGF, BNP, and
NGF-beta to the baseline values. Increased immunohistochemical labeling of HIF-1alpha,
VEGF, and BNP in the ventricular myocardium was observed in the banding group and
carvedilol again normalized the labeling. In conclusion, HIF-1alpha,
VEGF, and BNP
mRNA and
protein expression were up-regulated, while
NGF-beta
mRNA and
protein was downregulated in the rat model of pressure-overloaded
cardiac hypertrophy. Treatment with
carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha,
VEGF, BNP, and
NGF-beta in the hypertrophic myocardium.