Gene transfer of human prostacyclin synthase into the liver is effective for the treatment of pulmonary hypertension in rats.
BACKGROUND
As one of the future strategies of advanced pulmonary hypertension, intrinsic prostacyclin drug delivery using gene therapy may be useful. We investigated whether transfer of the prostacyclin synthase gene into the liver could ameliorate monocrotaline-induced pulmonary hypertension in rats.


METHODS
The human prostacyclin synthase gene was transfected into the liver of rats with monocrotaline-induced pulmonary hypertension. Hemodynamic indices, blood samples, lung tissues, and survival curves were evaluated between rats receiving the gene and control rats.


RESULTS
High levels of prostacyclin synthase gene expression were found in the hepatocytes of the prostacyclin synthase group. The level of 6-keto-prostaglandin F(1alpha) was significantly higher in the prostacyclin synthase group (prostacyclin synthase, 35.4 +/- 4.4 ng/mL; control, 22.3 +/- 3.3 ng/mL; P =.0436). The right ventricular/femoral artery pressure ratio was significantly lower in the prostacyclin synthase group than in the control group (prostacyclin synthase, 0.60 +/- 0.039; control, 0.88 +/- 0.051; P =.0036). The endothelin-1 levels in the lung tissues were significantly lower in the prostacyclin synthase group than in the control group (prostacyclin synthase, 10.42 +/- 2.01 pg/mg protein; control, 19.94 +/- 2.82 pg/mg protein; P =.0176). The survival ratio was significantly higher in the prostacyclin synthase group than the control group (P =.0375).


CONCLUSIONS
This drug delivery system using gene transfer can be considered as an alternative for continuous intravenous prostacyclin infusion for pulmonary hypertension.
Suhara
Hitoshi
H
Division of Cardiovascular Surgery, Department of Surgery, Osaka University Graduate School of Medicine, Japan.
Sawa
Yoshiki
Y
Fukushima
Norihide
N
Kagisaki
Koji
K
Yokoyama
Chieko
C
Tanabe
Tadashi
T
Ohtake
Shigeaki
S
Matsuda
Hikaru
H
D000818:Animals; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006976:Hypertension, Pulmonary / Q000401:mortality / Q000628:therapy*; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D018709:Statistics, Nonparametric; D015996:Survival Rate; D016896:Treatment Outcome
D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase