title: Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure.
abstract: BACKGROUND
  Heart failure following myocardial infarction (MI) is a significant cause of morbidity and mortality and remains a difficult therapeutic challenge. Hepatocyte growth factor (HGF) is a potent angiogenic and anti-apoptotic protein whose receptor is upregulated following MI. This study was designed to investigate the ability of HGF to prevent heart failure in a rat model of experimental MI.
  
  
  METHODS
  The rats underwent direct intramyocardial injection with replication-deficient adenovirus encoding HGF (n = 7) or null virus as control (n = 7) 3 weeks following ligation of the left anterior descending coronary artery. Analysis of the following was performed 3 weeks after injection: cardiac function by pressure-volume conductance catheter measurements; LV wall thickness; angiogenesis by Von Willebrand's factor staining; and apoptosis by the TUNEL assay. The expression levels of HGF and the anti-apoptotic factor Bcl-2 were analyzed by Western blot.
  
  
  RESULTS
  Adeno-HGF-treated animals had greater preservation of maximum LV pressure (HGF 77 +/- 3 vs. control 64 +/- 5 mmHg, p < 0.05), maximum dP/dt (3024 +/- 266 vs. 1907 +/- 360 mmHg/sec, p < 0.05), maximum dV/dt (133 +/- 20 vs. 84 +/- 6 muL/sec, p < 0.05), and LV border zone wall thickness (1.98 +/- 0.06 vs. 1.53 +/- 0.07 mm, p < 0.005). Angiogenesis was enhanced (151 +/- 10.0 vs. 90 +/- 4.5 endothelial cells/hpf, p < 0.005) and apoptosis was reduced (3.9 +/- 0.3 vs. 8.2 +/- 0.5%, p < 0.005). Increased expression of HGF and Bcl-2 protein was observed in the Adeno-HGF-treated group.
  
  
  CONCLUSIONS
  Overexpression of HGF 3 weeks post-MI resulted in enhanced angiogenesis, reduced apoptosis, greater preservation of ventricular geometry, and preservation of cardiac contractile function. This technique may be useful to treat or prevent postinfarction heart failure.
authors.affiliation: Department of Cardiothoracic Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Vasant
authors.initials: V
authors.lastname: Jayasankar
authors.forename: Y Joseph
authors.initials: YJ
authors.lastname: Woo
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Pirolli
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Bish
authors.forename: Mark F
authors.initials: MF
authors.lastname: Berry
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Burdick
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Gardner
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
mesh_terms: D000256:Adenoviridae; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D018014:Gene Transfer Techniques; D019254:Genes, bcl-2 / Q000187:drug effects; D005822:Genetic Vectors; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D008297:Male; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D043925:Angiogenesis Inducing Agents; D017228:Hepatocyte Growth Factor