{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:40:19Z","timestamp":1788867619577,"version":"build-2803163510"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              As partial pressure of oxygen (pO\n              <jats:sub>2<\/jats:sub>\n              ) rises with the first breath, the ductus arteriosus (DA) constricts, diverting blood flow to the pulmonary circulation. The DA's O\n              <jats:sub>2<\/jats:sub>\n              sensor resides within smooth muscle cells. The DA smooth muscle cells\u2019 mitochondrial electron transport chain (ETC) produces reactive oxygen species (ROS) in proportion to\u00a0oxygen tension, causing vasoconstriction by regulating redox\u2010sensitive ion channels and enzymes. To identify which ETC complex contributes most to DA O\n              <jats:sub>2<\/jats:sub>\n              sensing and determine whether ROS mediate O\n              <jats:sub>2<\/jats:sub>\n              sensing independent of metabolism, we used electron leak suppressors, S1QEL (suppressor of site I\n              <jats:sub>Q<\/jats:sub>\n              electron leak) and S3QEL (suppressor of site III\n              <jats:sub>Qo<\/jats:sub>\n              electron leak), which decrease ROS production by inhibiting electron leak from quinone sites I\n              <jats:sub>Q<\/jats:sub>\n              and III\n              <jats:sub>Qo<\/jats:sub>\n              , respectively.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The effects of S1QEL, S3QEL, and ETC inhibitors (rotenone and antimycin A) on DA tone, mitochondrial metabolism, O\n              <jats:sub>2<\/jats:sub>\n              \u2010induced changes in intracellular calcium, and ROS were studied in rabbit DA rings, and human and rabbit DA smooth muscle cells. S1QEL's effects on DA patency were assessed in rabbit kits, using micro computed tomography. In DA rings, S1QEL, but not S3QEL, reversed O\n              <jats:sub>2<\/jats:sub>\n              \u2010induced constriction (\n              <jats:italic>P<\/jats:italic>\n              =0.0034) without reducing phenylephrine\u2010induced constriction. S1QEL did not inhibit mitochondrial metabolism or ETC\u2010I activity. In human DA smooth muscle cells, S1QEL and rotenone inhibited O\n              <jats:sub>2<\/jats:sub>\n              \u2010induced increases in intracellular calcium (\n              <jats:italic>P<\/jats:italic>\n              =0.02 and 0.001, respectively), a surrogate for DA constriction. S1QEL inhibited O\n              <jats:sub>2<\/jats:sub>\n              \u2010induced ROS generation (\n              <jats:italic>P<\/jats:italic>\n              =0.02). In vivo, S1QEL prevented O\n              <jats:sub>2<\/jats:sub>\n              \u2010induced DA closure (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.0001).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              S1QEL, but not S3QEL, inhibited O\n              <jats:sub>2<\/jats:sub>\n              \u2010induced rises in ROS and DA constriction ex vivo and in vivo. DA O\n              <jats:sub>2<\/jats:sub>\n              sensing relies on pO\n              <jats:sub>2<\/jats:sub>\n              \u2010dependent changes in electron leak at site I\n              <jats:sub>Q<\/jats:sub>\n              in ETC\u2010I, independent of metabolism. S1QEL offers a therapeutic means to maintain DA patency.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.122.029131","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T11:45:26Z","timestamp":1687866326000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":14,"title":["Electron Leak From the Mitochondrial Electron Transport Chain Complex I at Site I\n            <sub>Q<\/sub>\n            Is Crucial for Oxygen Sensing in Rabbit and Human Ductus Arteriosus"],"prefix":"10.1161","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-6982","authenticated-orcid":false,"given":"Austin D.","family":"Read","sequence":"first","affiliation":[{"name":"Department of Medicine Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0486-8467","authenticated-orcid":false,"given":"Rachel E. T.","family":"Bentley","sequence":"additional","affiliation":[{"name":"Department of Medicine Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8170-1638","authenticated-orcid":false,"given":"Ashley Y.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Medicine Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1365-4228","authenticated-orcid":false,"given":"Jeffrey D.","family":"Mewburn","sequence":"additional","affiliation":[{"name":"Department of Medicine Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4046-1226","authenticated-orcid":false,"given":"Elahe","family":"Alizadeh","sequence":"additional","affiliation":[{"name":"Queen\u2019s CardioPulmonary Unit Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-5907","authenticated-orcid":false,"given":"Danchen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medicine Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6456-2470","authenticated-orcid":false,"given":"Patricia D. A.","family":"Lima","sequence":"additional","affiliation":[{"name":"Queen\u2019s CardioPulmonary Unit Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9760-342X","authenticated-orcid":false,"given":"Kimberly J.","family":"Dunham\u2010Snary","sequence":"additional","affiliation":[{"name":"Department of Medicine Queen\u2019s University Kingston Ontario Canada"},{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1844-7145","authenticated-orcid":false,"given":"Bernard","family":"Th\u00e9baud","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine University of Ottawa Ottawa Ontario Canada"},{"name":"Children\u2019s Hospital of Eastern Ontario Research Institute Ottawa Ontario Canada"},{"name":"Sinclair Centre for Regenerative Medicine Ottawa Hospital Research Institute Ottawa Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7175-3523","authenticated-orcid":false,"given":"Willard","family":"Sharp","sequence":"additional","affiliation":[{"name":"Department of Medicine The University of Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1106-3202","authenticated-orcid":false,"given":"Stephen L.","family":"Archer","sequence":"additional","affiliation":[{"name":"Department of Medicine Queen\u2019s University Kingston Ontario Canada"},{"name":"Queen\u2019s CardioPulmonary Unit Queen\u2019s University Kingston Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-015-1736-y"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.105.592063"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4615-9035-4_9"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.33.6.937"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.62.10.1030"},{"key":"e_1_3_1_7_2","first-page":"829","article-title":"Anatomical closure of the ductus arteriosus: a study in 35 specimens","volume":"128","author":"Ho SY","year":"1979","unstructured":"Ho SY, Anderson RH. 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