Document Detail


Extracellular superoxide dismutase overexpression can reverse the course of hypoxia-induced pulmonary hypertension.
MedLine Citation:
PMID:  22045221     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Mohamed N Ahmed; Yinzhong Zhang; Champa Codipilly; Nahla Zaghloul; Dhara Patel; Michael Wolin; Edmund J Miller
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-02-10
Journal Detail:
Title:  Molecular medicine (Cambridge, Mass.)     Volume:  18     ISSN:  1528-3658     ISO Abbreviation:  Mol. Med.     Publication Date:  2012  
Date Detail:
Created Date:  2012-02-13     Completed Date:  2012-06-01     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  9501023     Medline TA:  Mol Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  38-46     Citation Subset:  IM    
Affiliation:
Cohen Children's Medical Center, North Shore-Long Island Jewish Health System, New Hyde Park, New York, United States of America. mahmed2@nshs.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Anoxia / physiopathology*
Cells, Cultured
DNA, Complementary / genetics
Humans
Hypertension, Pulmonary / etiology*,  therapy*
Male
Mice
Mice, Transgenic
Superoxide Dismutase / genetics,  metabolism*
Transfection
Xanthine Oxidase / metabolism
Chemical
Reg. No./Substance:
0/DNA, Complementary; EC 1.15.1.1/Superoxide Dismutase; EC 1.17.3.2/Xanthine Oxidase
Comments/Corrections

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