title: Attenuation of monocrotaline-induced pulmonary hypertension by luminal adeno-associated virus serotype 9 gene transfer of prostacyclin synthase.
abstract: Idiopathic pulmonary arterial hypertension (iPAH) is associated with high morbidity and mortality. We evaluated whether luminal delivery of the human prostacyclin synthase (hPGIS) cDNA with adeno-associated virus (AAV) vectors could attenuate PAH. AAV serotype 5 (AAV5) and AAV9 vectors containing the hPGIS cDNA under the control of a cytomegalovirus-enhanced chicken β-actin (CB) promoter or vehicle (saline) were instilled into lungs of rats. Two days later, rats were injected with monocrotaline (MCT, 60 mg/kg) or saline. Biochemical, hemodynamic, and morphologic assessments were performed when the rats developed symptoms (3-4 weeks) or at 6 weeks. Luminal (airway) administration of AAV5 and AAV9CBhPGIS vectors (MCT-AAV5 and MCT-AAV9 rats) significantly increased plasma levels of 6-keto-PGF1(α) as compared with MCT-controls, and closely resembled levels measured in rats not treated with MCT (saline-saline). Right ventricular (RV)/left ventricular (LV)+septum (S) ratios and RV systolic pressure (RVSP) were greater in MCT-control rats than in saline-saline rats, whereas the ratios and RVSP in MCT-AAV5CBhPGIS and MCT-AAV9CBhPGIS rats were similar to saline-saline rats. Thickening of the muscular media of small pulmonary arteries of MCT-control rats was detected in histological sections, whereas the thickness of the muscular media in MCT-AAV5CBhPGIS and MCT-AAV9CBhPGIS rats was similar to saline-saline controls. In experiments with different promoters, a trend toward increased levels of PGF1(α) expression was detected in lung homogenates, but not plasma, of MCT-treated rats transduced with an AAV9-hPGIS vector containing a CB promoter. This correlated with significant reductions in the RV/LV+S ratio and RVSP in MCT-AAV9CBhPGIS rats that resembled levels in saline-saline rats. No changes in levels of PGF1(α), RV/LV+S, or RVSP were detected in rats transduced with AAV9-hPGIS vectors containing a modified CB promoter (CB7) or a distal epithelial cell-specific promoter (CC10). Thus, AAV9CBhPGIS vectors prevented development of MCT-induced PAH and associated pulmonary vascular remodeling.
authors: 1 Division of Pulmonary and Critical Care, Department of Medicine, University of Arkansas for Medical Sciences , Little Rock, AR 72205.
authors: Igor B
authors: IB
authors: Gubrij
authors: Sara Rebecca
authors: SR
authors: Martin
authors: Amanda K
authors: AK
authors: Pangle
authors: Richard
authors: R
authors: Kurten
authors: Larry G
authors: LG
authors: Johnson
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics*; D004790:Enzyme Induction; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis / Q000235:genetics*; D016686:Monocrotaline; D011401:Promoter Regions, Genetic; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic; D066253:Vascular Remodeling
chemical_list: D016686:Monocrotaline; D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase