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We investigated the hypothesis that a decrease in expression and activity of mitochondrial localized manganese superoxide dismutase (MnSOD) in pulmonary artery endothelial cells (PAEC) increases oxidative stress and impairs eNOS function in PPHN. We isolated PAEC and pulmonary arteries from fetal lambs with PPHN induced by prenatal ductus arteriosus ligation or sham ligation (control). We investigated MnSOD expression and activity, tyrosine nitration of MnSOD, and mitochondrial O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>levels in PAEC from control and PPHN lambs. We introduced exogenous MnSOD via an adenoviral vector (ad-MnSOD) transduction into PAEC and pulmonary arteries of PPHN lambs. The effect of ad-MnSOD was investigated on: mitochondrial O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>levels, MnSOD and eNOS expression and activity, intracellular hydrogen peroxide (H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>) levels, and catalase expression in PAEC. MnSOD mRNA and protein levels and activity were decreased and MnSOD tyrosine nitration was increased in PPHN-PAEC. ad-MnSOD transduction of PPHN-PAEC increased its activity two- to threefold, decreased mitochondrial O<jats:sub>2<\/jats:sub><jats:sup>\u2212<\/jats:sup>levels, and increased H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>levels and catalase expression. ad-MnSOD transduction improved eNOS expression and function and the relaxation response of PPHN pulmonary arteries. Our observations suggest that decreased MnSOD expression and activity contribute to the endothelial dysfunction observed in PPHN.<\/jats:p>","DOI":"10.1152\/ajplung.00098.2012","type":"journal-article","created":{"date-parts":[[2012,9,8]],"date-time":"2012-09-08T05:23:02Z","timestamp":1347081782000},"page":"L870-L879","source":"Crossref","is-referenced-by-count":61,"title":["Decreases in manganese superoxide dismutase expression and activity contribute to oxidative stress in persistent pulmonary hypertension of the newborn"],"prefix":"10.1152","volume":"303","author":[{"given":"Adeleye J.","family":"Afolayan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Cardiovascular Research Center and Children's Research Institute, Medical College of Wisconsin, Milwaukee, Wisconsin;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Eis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Cardiovascular Research Center and 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