{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T09:36:10Z","timestamp":1790415370199,"version":"4.1.0"},"reference-count":42,"publisher":"American Physiological Society","issue":"1","funder":[{"name":"NIH","award":["RO3HD-06581"],"award-info":[{"award-number":["RO3HD-06581"]}]},{"name":"NIH","award":["RO1HL-057268"],"award-info":[{"award-number":["RO1HL-057268"]}]},{"name":"NIH","award":["RO1HD072929"],"award-info":[{"award-number":["RO1HD072929"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:p>Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O<jats:sub>2<\/jats:sub>alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-\u03b3 coactivator 1-\u03b1 (PGC-1\u03b1) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O<jats:sub>2<\/jats:sub>was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of Fi<jats:sub>O<jats:sub>2<\/jats:sub><\/jats:sub>, partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN-PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O<jats:sub>2<\/jats:sub>amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen.<\/jats:p>","DOI":"10.1152\/ajplung.00392.2014","type":"journal-article","created":{"date-parts":[[2015,10,31]],"date-time":"2015-10-31T00:36:27Z","timestamp":1446251787000},"page":"L40-L49","source":"Crossref","is-referenced-by-count":66,"title":["Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension"],"prefix":"10.1152","volume":"310","author":[{"given":"Adeleye J.","family":"Afolayan","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Children's Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Eis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children's Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxwell","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children's Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Michalkiewicz","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children's Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru-Jeng","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children's Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satyan","family":"Lakshminrusimha","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Buffalo, Buffalo, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girija G.","family":"Konduri","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children's Research Institute and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00098.2012"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00264.2013"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.113662"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M203154200"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1996.271.5.C1424"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.281.6.E1340"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0b013e328328d0a4"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183804"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2008.162"},{"key":"B10","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1542\/peds.59.2.205","volume":"59","author":"Fox WW","year":"1977","journal-title":"Pediatrics"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.1773"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2009.171"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/er.2006-0037"},{"key":"B14","first-page":"540","volume":"4","author":"Hirata Y","year":"2001","journal-title":"JAMA"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1177604"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00837.2002"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/jp.2013.83"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1159\/000014274"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00245.2002"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1542\/peds.113.3.559"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00425.2006"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e3181bab0c7"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000191136.69142.8c"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000159575.58834.8D"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501485200"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1126\/science.1079368"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1086\/674767"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ijo.0802905"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.109512"},{"key":"B30a","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2008.07.018"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1119(01)00809-5"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S0167-4781(02)00343-3"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308686101"},{"key":"B33a","doi-asserted-by":"publisher","DOI":"10.1590\/S0074-02762005000900004"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00112.2002"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/35072063"},{"key":"B36","first-page":"353A","volume":"49","author":"Steinhorn RH","year":"2001","journal-title":"Pediatr Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304471200"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00200.2012"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00316.2010"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)03309-7"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)04100-1"}],"container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajplung.00392.2014","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,24]],"date-time":"2022-05-24T22:20:26Z","timestamp":1653430826000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajplung.00392.2014"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,1,1]]}},"alternative-id":["10.1152\/ajplung.00392.2014"],"URL":"https:\/\/doi.org\/10.1152\/ajplung.00392.2014","relation":{},"ISSN":["1040-0605","1522-1504"],"issn-type":[{"value":"1040-0605","type":"print"},{"value":"1522-1504","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,1,1]]}}}