In vivo hepatocyte growth factor gene transfer reduces myocardial ischemia-reperfusion injury through its multiple actions.
BACKGROUND
Hepatocyte growth factor (HGF) is reported to protect the heart against ischemia-reperfusion injury. However, whether in vivo adenovirus-mediated HGF gene transfer before ischemia is protective against ischemia-reperfusion and its precise mechanisms are still unknown.


RESULTS
By using a rabbit model of ischemia-reperfusion injury, we demonstrate that HGF gene transfer is cardioprotective through its multiple beneficial actions, such as angiogenesis, Bcl-2 overexpression, and decreasing hydroxyl radicals, deoxyuride-5'-triphosphate biotin nick end labeling (TUNEL)-positive myocytes, and fibrotic area. After HGF gene transfer, the rabbits underwent 30 minutes of coronary occlusion and 30 minutes, 4 hours, 48 hours, and 14 days of reperfusion. The infarct size at 48 hours of reperfusion was significantly reduced in the HGF group (13.4% +/- 2.3%) compared with that in the LacZ group (36.5% +/- 2.0%) and saline group (40.3% +/- 3.2%). At 14 days of reperfusion, HGF gene transfer improved left ventricular ejection fraction and fractional shortening, reduced the fibrotic area, and increased the capillary density in the risk area. At 4 hours of reperfusion, Bcl-2 protein was overexpressed and the incidence of TUNEL-positive myocytes was significantly decreased in the risk area in the HGF group compared with the LacZ and saline groups. The myocardial interstitial 2,5-dihydroxybenzoic acid level, an indicator of hydroxyl radical, increased during 30 minutes of ischemia and 30 minutes of reperfusion in the LacZ and saline groups, and was significantly inhibited in the HGF group.


CONCLUSIONS
HGF gene therapy may be a novel therapeutic strategy against unstable angina pectoris or severe angina pectoris, which may progress to acute myocardial infarction.
Chen
Xue-Hai
XH
Department of Cardiology, Regeneration and Advanced Medical Science, Gifu University, Gifu, Japan.
Minatoguchi
Shinya
S
Kosai
Kenichiro
K
Yuge
Kentaro
K
Takahashi
Tomoyuki
T
Arai
Masazumi
M
Wang
Ningyuan
N
Misao
Yu
Y
Lu
Chuanjiang
C
Onogi
Hirohito
H
Kobayashi
Hiroyuki
H
Yasuda
Shinji
S
Ezaki
Masayasu
M
Ushikoshi
Hiroaki
H
Takemura
Genzou
G
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D016896:Treatment Outcome
D017228:Hepatocyte Growth Factor