title: 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Education and Research, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Kou-Gi
authors.initials: KG
authors.lastname: Shyu
authors.forename: Ming-Jen
authors.initials: MJ
authors.lastname: Lu
authors.forename: Hang
authors.initials: H
authors.lastname: Chang
authors.forename: Hsien-Yi
authors.initials: HY
authors.lastname: Sun
authors.forename: Bao-Wei
authors.initials: BW
authors.lastname: Wang
authors.forename: Peiliang
authors.initials: P
authors.lastname: Kuan
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D004452:Echocardiography; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009206:Myocardium / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D011412:Propanolamines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D048348:Reverse Transcription; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D016277:Ventricular Function, Left
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011412:Propanolamines; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000077261:Carvedilol; D020097:Natriuretic Peptide, Brain