title: Gene transfer therapy by either type 1 or type 2 adeno-associated virus expressing human prostaglandin I2 synthase gene is effective for treatment of pulmonary arterial hypertension.
abstract: Prostaglandin I(2) (PGI(2)) plays an important role in the clinical treatment of pulmonary arterial hypertension (PAH). However, the administration of PGI(2) involves continuous intravenous infusion using an indwelling catheter, which limits the patient's quality of life and increases the risk of infection. We therefore investigated whether human PGI(2) synthase (hPGIS) gene transfer using an adeno-associated virus (AAV) vector is still effective in a mouse model of PAH and tested for differences in the therapeutic efficacy of PAH among AAV serotypes. The PAH was induced by subjecting mice to hypoxia (10% O(2)). Type 1 AAV expressing hPGIS (AAV1-hPGIS) or type 2 AAV expressing hPGIS (AAV2-hPGIS) was injected into the thigh muscle of mice. Both vectors expressing hPGIS produced strong hPGIS protein expression in the mouse thigh skeletal muscles after 8 weeks of hypoxia. The administration of AAV1-hPGIS or AAV2-hPGIS also significantly inhibited the hypoxia-induced increase in right ventricular systolic pressure, the ratio of right ventricular weight to body weight (RV/BW), and the ratio of RV weight to left ventricular plus septal weight (RV/LV + S), and significantly attenuated the hypoxia-induced increase in medial wall thickness of peripheral pulmonary arteries. Furthermore, there were no significant differences in the degree of amelioration in RV systolic pressure, RV/BW, RV/LV + S, and percentage of wall thickness of peripheral pulmonary arteries between AAV1-hPGIS and AAV2-hPGIS administrations. In conclusion, we revealed that type 1 and type 2 AAV are equally effective for the treatment of PAH in a hypoxia-induced mouse model. Gene-transfer therapy using AAV expressing hPGIS is, therefore, a potential therapeutic breakthrough for PAH.
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kataoka
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawakami
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tamura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yoshino
authors.forename: Toru
authors.initials: T
authors.lastname: Satoh
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tanabe
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics*; D065627:Familial Primary Pulmonary Hypertension; D015316:Genetic Therapy; D006801:Humans; D006976:Hypertension, Pulmonary / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000628:therapy; D019746:Intramolecular Oxidoreductases / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011651:Pulmonary Artery / Q000473:pathology; D013599:Systole
chemical_list: D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase