Gene transfer of hepatocyte growth factor with prostacyclin synthase in severe pulmonary hypertension of rats.
OBJECTIVE
Hepatocyte growth factor (HGF) is a multi-potent growth factor, which has anti-fibrotic effects for lung injuries. In this study, we investigated whether human HGF gene transfer may attenuate the medial hypertrophy of pulmonary arteries and enhance the ameliorating effect of prostacyclin in monocrotaline (MCT)-induced pulmonary hypertension in rats.


RESULTS
The day before MCT injection, HVJ-liposome complex with the cDNA encoding HGF gene (H group), PGIS gene (P group), and both HGF and PGIS gene (HP group) were transfected to the liver of rats as drug delivery system for the lung. Rats transfected with control vector served as controls (C group). Twenty-eight days after MCT injection, histological examination showed marked thickening of medial wall of pulmonary arteries and right ventricular hypertrophy. Percent medial wall thickness (%WT) of peripheral pulmonary arteries, pressure ratio of the right ventricle (RV) to the left ventricle (LV), and weight ratio of the RV to the LV plus septum were significantly increased in the control. Percent medial wall thickness was significantly ameliorated in H group and HP group in comparison with C group. Pressure and weight ratio of RV to LV was significantly ameliorated in P group and HP group in comparison with C group, and was significantly ameliorated in HP group than P group.


CONCLUSIONS
In vivo gene transfection with HGF gene attenuated the medial hypertrophy of pulmonary arteries and enhanced the ameliorating effect of prostacyclin for pulmonary hypertension in MCT rats. Thus, gene therapy with HGF and PGIS may be a promising strategy for severe pulmonary hypertension.
Ono
Masamichi
M
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Sawa
Yoshiki
Y
Fukushima
Norihide
N
Suhara
Hitoshi
H
Nakamura
Toshikazu
T
Yokoyama
Chieko
C
Tanabe
Tadashi
T
Matsuda
Hikaru
H
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D017228:Hepatocyte Growth Factor / Q000032:analysis / Q000235:genetics*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000517:prevention & control; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D016686:Monocrotaline; D009929:Organ Size / Q000502:physiology; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection / Q000379:methods*
D017228:Hepatocyte Growth Factor; D016686:Monocrotaline; D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase