Carvedilol modulates the expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in a rat model of volume-overload heart failure.

Abstract

BACKGROUND:

The use of beta-blockers has emerged as a beneficial treatment for congestive heart failure. Hypoxia-inducible factor-1alpha (HIF-1alpha) is tightly regulated in the ventricular myocardium. However, the expression of HIF-1alpha in chronic heart failure resulting from volume overload and after treatment with beta-blocker is little known.

METHODS AND RESULTS:

To test the hypothesis that HIF-1alpha plays a role in the failing myocardium because of volume overload, an aorta-caval shunt was created for 4 weeks in adult Sprague-Dawley rats to induce volume-overload heart failure. Carvedilol at 50 mg/kg body weight per day after surgery was given. The heart weight and body weight ratio increased from 2.6 +/- 0.3 in the sham group to 3.9 +/- 0.7 (P < .001) in the shunt group. Left ventricular end-diastolic dimension increased from 6.5 +/- 0.5 mm to 8.7 +/- 0.6 mm (P < .001). Treatment with carvedilol in the shunt group reversed the heart weight and ventricular dimension to the baseline values. Western blot showed that HIF-1alpha, vascular endothelial growth factor (VEGF), and brain natriuretic peptide (BNP) proteins were upregulated and nerve growth factor-beta (NGF-beta) downregulated in the shunt group. Real-time polymerase chain reaction showed that mRNA of HIF-1alpha, VEGF, and BNP increased and mRNA of NGF-beta decreased in the shunt 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 shunt group and carvedilol again normalized the labeling.

CONCLUSION:

HIF-1alpha and VEGF mRNA and protein expression were upregulated in the rat model of volume-overload heart failure. Treatment with carvedilol is associated with a reversal of abnormal regulation of HIF-1alpha and VEGF in the failing ventricular myocardium.

• Authors: Kou-Gi Shyu, Ming-Jen Lu, Hang Chang, Hsien-Yi Sun, Bao-Wei Wang, Peiliang Kuan
• Journal: Journal of cardiac failure (J Card Fail) Vol. 11 Issue 2 Pg. 152-9 (Mar 2005) ISSN: 1071-9164 [Print] United States
• PMID: 15732037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic beta-Antagonists
• Carbazoles
• Hypoxia-Inducible Factor 1, alpha Subunit
• Propanolamines
• RNA, Messenger
• Transcription Factors
• Vascular Endothelial Growth Factor A
• Carvedilol
• Natriuretic Peptide, Brain

Topics

• Adrenergic beta-Antagonists (therapeutic use)
• Animals
• Blotting, Western
• Carbazoles (therapeutic use)
• Carvedilol
• Echocardiography
• Heart Failure (diagnostic imaging, drug therapy, etiology)
• Hypoxia-Inducible Factor 1, alpha Subunit
• Myocardium (metabolism)
• Natriuretic Peptide, Brain (biosynthesis)
• Polymerase Chain Reaction
• Propanolamines (therapeutic use)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcription
• Transcription Factors (biosynthesis)
• Up-Regulation
• Vascular Endothelial Growth Factor A (biosynthesis)
• Ventricular Function, Left