title: Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat.
abstract: OBJECTIVE
  The therapeutic utility of hypoxia-inducible factor-1 (HIF-1) transcriptional regulatory system for ischemic hindlimb has been demonstrated. It is not yet known whether this transcriptional regulatory system can be used as a therapeutic strategy to enhance collateral vessel formation in myocardial tissues, where acute hypoxia occurs due to inadequate perfusion. We aimed to test the hypothesis that exogenous administration of HIF-1alpha/VP16 could enhance collateral vessel formation in a rat acute myocardial infarction model.
  
  
  METHODS
  Sprague-Dawley rats received ligation of the proximal left anterior descending coronary artery to induce acute myocardial infarction. Immediately after the ligation, 50 microg total plasmid DNA (control, plasmid encoding human vascular endothelial growth factor (pVEGF(165)), or pHIF-1alpha/VP16) was injected into the infarct area at three locations.
  
  
  RESULTS
  Reverse transcription-polymerase chain reaction (RT-PCR) showed the presence of HIF-1alpha and VEGF mRNA in the myocardium, but not in other organs at days 3 and 7. The infarct size significantly decreased from 37+/-4% (control) to 24+/-2% in the VEGF-treated group and 23+/-2% in the HIF-1alpha/VP16 treated group (P<0.05). Capillary density also significantly increased from 550+/-75/mm(2) (control) to 850+/-75/mm(2) in the VEGF group and 850+/-50/mm(2) in the HIF-1alpha/VP16-treated group (P<0.01). Combined therapy with HIF-1alpha/VP16 and VEGF resulted in higher capillary density (1230+/-50/mm(2)) than treatment with either therapy alone. Regional myocardial blood flow was also higher in the treated groups than in the control. Plasma levels of VEGF were also significantly higher in the HIF-1alpha/VP16 and VEGF-treated group than in the control group.
  
  
  CONCLUSIONS
  The HIF-1alpha/VP16 hybrid transcription factor is able to reduce infarct size and enhance neovascularization in an acute ischemic myocardium. The potency of VEGF and HIF-1alpha/VP16 hybrid as therapeutic angiogenic factors in acute hypoxic myocardium is similar.
authors.affiliation: Division of Cardiology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
authors.forename: Kou Gi
authors.initials: KG
authors.lastname: Shyu
authors.forename: Mei Ti
authors.initials: MT
authors.lastname: Wang
authors.forename: Bao Wei
authors.initials: BW
authors.lastname: Wang
authors.forename: Chih Chuna
authors.initials: CC
authors.lastname: Chang
authors.forename: Jyh Gang
authors.initials: JG
authors.lastname: Leu
authors.forename: Peiliang
authors.initials: P
authors.lastname: Kuan
authors.forename: Hang
authors.initials: H
authors.lastname: Chang
mesh_terms: D000818:Animals; D002196:Capillaries; D003097:Collateral Circulation; D004247:DNA / Q000008:administration & dosage*; D016228:Endothelial Growth Factors / Q000235:genetics; D005047:Etoposide; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007267:Injections; D008222:Lymphokines / Q000235:genetics; D008297:Male; D023421:Models, Animal; D009203:Myocardial Infarction / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D005047:Etoposide; D004247:DNA