title: Extracellular superoxide dismutase overexpression can reverse the course of hypoxia-induced pulmonary hypertension.
abstract: Hypoxia leads to free radical production, which has a pivotal role in the pathophysiology of pulmonary hypertension (PH). We hypothesized that treatment with extracellular superoxide dismutase (EC-SOD) could ameliorate the development of PH induced by hypoxia. In vitro studies using pulmonary microvascular endothelial cells showed that cells transfected with EC-SOD had significantly less accumulation of xanthine oxidase and reactive oxygen species than nontransfected cells after hypoxia exposure for 24 h. To study the prophylactic role of EC-SOD, adult male wild-type (WT) and transgenic (TG) mice, with lung-specific overexpression of human EC-SOD (hEC-SOD), were exposed to fraction of inspired oxygen (FiO(2)) 10% for 10 d. After exposure, right ventricular systolic pressure (RVSP), right ventricular mass (RV/S + LV), pulmonary vascular wall thickness (PVWT) and pulmonary artery contraction/relaxation were assessed. TG mice were protected against PH compared with WT mice with significantly lower RVSP (23.9 ± 1.24 versus 47.2 ± 3.4), RV/S + LV (0.287 ± 0.015 versus 0.335 ± 0.022) and vascular remodeling, indicated by PVWT (14.324 ± 1.107 versus 18.885 ± 1.529). Functional studies using pulmonary arteries isolated from mice indicated that EC-SOD prevents hypoxia-mediated attenuation of nitric oxide-induced relaxation. Therapeutic potential was assessed by exposing WT mice to FiO(2) 10% for 10 d. Half of the group was transfected with plasmid containing cDNA encoding human EC-SOD. The remaining animals were transfected with empty vector. Both groups were exposed to FiO(2) 10% for a further 10 d. Transfected mice had significantly reduced RVSP (18.97 ± 1.12 versus 41.3 ± 1.5), RV/S + LV (0.293 ± 0.012 versus 0.372 ± 0.014) and PVWT (12.51 ± 0.72 versus 18.98 ± 1.24). On the basis of these findings, we concluded that overexpression of EC-SOD prevents the development of PH and ameliorates established PH.
authors: Cohen Children's Medical Center, North Shore-Long Island Jewish Health System, New Hyde Park, New York, United States of America. mahmed2@nshs.edu
authors: Mohamed N
authors: MN
authors: Ahmed
authors: Yinzhong
authors: Y
authors: Zhang
authors: Champa
authors: C
authors: Codipilly
authors: Nahla
authors: N
authors: Zaghloul
authors: Dhara
authors: D
authors: Patel
authors: Michael
authors: M
authors: Wolin
authors: Edmund J
authors: EJ
authors: Miller
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000628:therapy*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase