Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats.
BACKGROUND
Prostacyclin is a potent vasodilator that also inhibits platelet adhesion and cell growth. We investigated whether in vivo gene transfer of human prostacyclin synthase (PGIS) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats.


RESULTS
The cDNA encoding PGIS was intratracheally transfected into the lungs of rats by the hemagglutinating virus of Japan-liposome method. Rats transfected with control vector lacking the PGIS gene served as controls. Three weeks after MCT injection, mean pulmonary arterial pressure and total pulmonary resistance had increased significantly; the increases were significantly attenuated in PGIS gene-transfected rats compared with controls [mean pulmonary arterial pressure, 31+/-1 versus 35+/-1 mm Hg (-12%); total pulmonary resistance, 0.087+/-0.01 versus 0.113+/-0.01 mm Hg x mL x min(-1) x kg(-1) (-23%), both P:<0.05]. Systemic arterial pressure and heart rate were unaffected. Histologically, PGIS gene transfer inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection. PGIS immunoreactivity was intense predominantly in the bronchial epithelium and alveolar cells. Lung tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, were significantly increased for >/=1 week after transfer of PGIS gene. The Kaplan-Meier survival curves demonstrated that repeated transfer of PGIS gene every 2 weeks increased survival rate in MCT rats (log-rank test, P:<0.01).


CONCLUSIONS
Intratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.
Nagaya
N
N
Division of Cardiology, Department of Medicine, National Cardiovascular Center, Osaka University Medical School, Osaka, Japan.
Yokoyama
C
C
Kyotani
S
S
Shimonishi
M
M
Morishita
R
R
Uematsu
M
M
Nishikimi
T
T
Nakanishi
N
N
Ogihara
T
T
Yamagishi
M
M
Miyatake
K
K
Kaneda
Y
Y
Tanabe
T
T
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000008:administration & dosage* / Q000235:genetics*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000008:administration & dosage* / Q000235:genetics*; D008081:Liposomes; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D018108:Respirovirus / Q000235:genetics; D016019:Survival Analysis
D008081:Liposomes; D015121:6-Ketoprostaglandin F1 alpha; D016686:Monocrotaline; D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase