Induction of angiogenesis and inhibition of apoptosis by hepatocyte growth factor effectively treats postischemic heart failure.
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.
Jayasankar
Vasant
V
Department of Cardiothoracic Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Woo
Y Joseph
YJ
Pirolli
Timothy J
TJ
Bish
Lawrence T
LT
Berry
Mark F
MF
Burdick
Jeffrey
J
Gardner
Timothy J
TJ
Sweeney
H Lee
HL
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
D043925:Angiogenesis Inducing Agents; D017228:Hepatocyte Growth Factor