Adenoassociated Virus–Mediated Prostacyclin Synthase Expression Prevents Pulmonary Arterial Hypertension in Rats

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 50; no. 3; pp. 531 - 536
• Main Authors: Ito, Takayuki, Okada, Takashi, Mimuro, Jun, Miyashita, Hiroshi, Uchibori, Ryosuke, Urabe, Masashi, Mizukami, Hiroaki, Kume, Akihiro, Takahashi, Masafumi, Ikeda, Uichi, Sakata, Yoichi, Shimada, Kazuyuki, Ozawa, Keiya
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.09.2007; Hagerstown, MD Lippincott
• Subjects: 6-Ketoprostaglandin F1 alpha - blood; 6-Ketoprostaglandin F1 alpha - metabolism; Adeno-associated virus; Animals; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Pressure; Cardiology. Vascular system; Cell Line; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Dependovirus - genetics; Epoprostenol - metabolism; Experimental diseases; Feasibility Studies; Gene Transfer Techniques; Genetic Vectors - administration & dosage; Heart Rate; Humans; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; Hypertension, Pulmonary - prevention & control; Hypertrophy; Hypertrophy, Right Ventricular - pathology; Injections, Intramuscular; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Male; Medical sciences; Monocrotaline; Pulmonary Artery - pathology; Rats; Rats, Wistar; Survival Analysis; remodeling; Intravenous administration; Prostaglandin I2; Rat; Catheter; Cardiovascular disease; Metabolic pathway; Vascular resistance; Complication; Arterial pressure; Human; Hypertension; Respiratory disease; Rodentia; pulmonary; Survival; Pulmonary artery; Pulmonary hypertension; Virus; Vertebrata; Mammalia; Treatment; Animal; Feasibility; Transduction; prostacyclin synthase; Genome; Gene therapy; Comparative study
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.107.091348

Prostacyclin synthase (PGIS) is the final committed enzyme in the metabolic pathway of prostacyclin production. The therapeutic option of intravenous prostacyclin infusion in patients with pulmonary arterial hypertension is limited by the short half-life of the drug and life-threatening catheter-related complications. To develop a better delivery system for prostacyclin, we examined the feasibility of intramuscular injection of an adenoassociated virus (AAV) vector expressing PGIS for preventing monocrotaline-induced pulmonary arterial hypertension in rats. We developed an AAV serotype 1–based vector carrying a human PGIS gene (AAV-PGIS). AAV-PGIS or the control AAV vector expressing enhanced green fluorescent protein was injected into the anterior tibial muscles of 3-week–old male Wistar rats; this was followed by the monocrotaline administration at 7 weeks. Eight weeks after injecting the vector, the plasma levels of 6-keto-prostaglandin F1α increased in a vector dose-dependent manner. At this time point, the PGIS transduction (1×10 genome copies per body) significantly decreased mean pulmonary arterial pressure (33.9±2.4 versus 46.1±3.0 mm Hg; P<0.05), pulmonary vascular resistance (0.26±0.03 versus 0.41±0.03 mm Hg · mL · min · kg; P<0.05), and medial thickness of the peripheral pulmonary artery (14.6±1.5% versus 23.5±0.5%; P<0.01) as compared with the controls. Furthermore, the PGIS-transduced rats demonstrated significantly improved survival rates as compared with the controls (100% versus 50%; P<0.05) at 8 weeks postmonocrotaline administration. An intramuscular injection of AAV-PGIS prevents monocrotaline-pulmonary arterial hypertension in rats and provides a new therapeutic alternative for preventing pulmonary arterial hypertension in humans.