{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:23:03Z","timestamp":1790810583587,"version":"4.1.0"},"reference-count":87,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,7,16]]},"abstract":"<jats:sec id=\"jah39850-sec-0001\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Endothelial cell (EC) dysfunction involves reduced nitric oxide (NO) bioavailability due to NO synthase uncoupling linked to increased oxidation and reduced cofactor availability. Loss of endothelial function and NO bioavailability are associated with inflammation, including leukocyte activation. Eicosapentaenoic acid (EPA) administered as icosapent ethyl reduced cardiovascular events in REDUCE\u2010IT (Reduction of Cardiovascular Events With Icosapent Ethyl\u2013Intervention Trial) in relation to on\u2010treatment EPA blood levels. The mechanisms of cardiovascular protection for EPA remain incompletely elucidated but likely involve direct effects on the endothelium.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec id=\"jah39850-sec-0002\" xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              In this study, human ECs were treated with EPA and challenged with the cytokine IL\u20106 (interleukin\u20106). Proinflammatory responses in the ECs were confirmed by ELISA capture of sICAM\u20101 (soluble intercellular adhesion molecule\u20101) and TNF\u2010\u03b1 (tumor necrosis factor\u2010\u03b1). Global protein expression was determined using liquid chromatography\u2013mass spectrometry tandem mass tag. Release kinetics of NO and peroxynitrite were monitored using porphyrinic nanosensors. IL\u20106 challenge induced proinflammatory responses from the ECs as evidenced by increased release of sICAM\u20101 and TNF\u2010\u03b1, which correlated with a loss of NO bioavailability. ECs pretreated with EPA modulated expression of 327 proteins by &gt;1\u2010fold (\n              <jats:italic toggle=\"no\">P<\/jats:italic>\n              &lt;0.05), compared with IL\u20106 alone. EPA augmented expression of proteins involved in NO production, including heme oxygenase\u20101 and dimethylarginine dimethylaminohydrolase\u20101, and 34 proteins annotated as associated with neutrophil degranulation. EPA reversed the endothelial NO synthase uncoupling induced by IL\u20106 as evidenced by an increased [NO]\/[peroxynitrite] release ratio (\n              <jats:italic toggle=\"no\">P<\/jats:italic>\n              &lt;0.05).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec id=\"jah39850-sec-0003\" xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">These direct actions of EPA on EC functions during inflammation may contribute to its distinct cardiovascular benefits.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.034076","type":"journal-article","created":{"date-parts":[[2024,7,3]],"date-time":"2024-07-03T10:41:51Z","timestamp":1720003311000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":32,"title":["Eicosapentaenoic Acid Improves Endothelial Nitric Oxide Bioavailability Via Changes in Protein Expression During Inflammation"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0913-2865","authenticated-orcid":false,"given":"Samuel C. R.","family":"Sherratt","sequence":"first","affiliation":[{"name":"University of New Hampshire","place":["Durham, USA"]},{"name":"Elucida Research","place":["Beverly, USA"]},{"name":"Icahn School of Medicine at Mount Sinai","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1502-502X","authenticated-orcid":false,"given":"Peter","family":"Libby","sequence":"additional","affiliation":[{"name":"Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2624-6573","authenticated-orcid":false,"given":"Hazem","family":"Dawoud","sequence":"additional","affiliation":[{"name":"Ohio University","place":["Athens, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1278-6245","authenticated-orcid":false,"given":"Deepak L.","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Icahn School of Medicine at Mount Sinai","place":["New York, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-1852","authenticated-orcid":false,"given":"R. Preston","family":"Mason","sequence":"additional","affiliation":[{"name":"Elucida Research","place":["Beverly, USA"]},{"name":"Harvard Medical School","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.306301"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-1-4557-2296-9.00003-8"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.602532"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.101506"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000131515.03336.f8"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2006.10.009"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200314172"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0b013e32833992ef"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000115557.25127.8D"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137244"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-010-0118-2"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.3844\/ajptsp.2019.7.16"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.04.061"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2021.04.059"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-022-01075-x"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2012.05.031"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2011.04.015"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1812792"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.313286"},{"key":"e_1_3_2_21_2","first-page":"29","article-title":"Eicosapentaenoic acid: atheroprotective properties and the reduction of atherosclerotic cardiovascular disease events","volume":"5","author":"Pisaniello AD","year":"2020","unstructured":"Pisaniello AD, Nicholls SJ, Ballantyne CM, Bhatt DL, Wong ND. Eicosapentaenoic acid: atheroprotective properties and the reduction of atherosclerotic cardiovascular disease events. Eur Med J. 2020;5:29\u201336.","journal-title":"Eur Med J"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehaa652"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/ehjci\/jead063"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2016.10.002"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.171736"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40256-012-0002-3"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2015.07.035"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2020.183254"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.04.118"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.plefa.2021.102337"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.122.029109"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114629"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.84"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2017.12.023"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/358676a0"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.147"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm453"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1039\/C5MB00663E"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1543"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0607260103"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1097\/FJC.0000000000000251"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18122563"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi9007098"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202101621R"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv114"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.27.1.4862"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.20.5.1209"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/89068"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3726"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI4165"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03392-8"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.04.091"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds131"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.65.5.1238"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-022-00736-w"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.101890"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2013.12.273"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq373"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12975-019-00772-1"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.120.000096"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.245530"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2008.07.029"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2013.10.011"},{"key":"e_1_3_2_65_2","unstructured":"Daida H Nishizaki Y Iwata H Inoue T Hirayama A Kimura K Ozaki Y Murohara T Ueshima K Kuwabara Y et\u00a0al. Randomized trial for evaluation in secondary prevention efficacy of combination therapy\u2014statin and eicosapentaenoic acid (RESPECT\u2010EPA). Annual Scientific Sessions of the American Heart Association. 2022."},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI97943"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40119-019-0131-8"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2019.01.022"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1186\/1710-1492-2-3-98"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2015-207604"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.200161"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb13653.x"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000032114.68919.EF"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401152"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-5-215"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.013201"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801213200"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.818302"},{"key":"e_1_3_2_79_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.161067"},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-04-710632"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12710"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81660"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.50.33342"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2008.03191.x"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(86)90246-7"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI112261"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/suaa119"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103040"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.123.034076","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T09:51:07Z","timestamp":1747302667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.123.034076"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,16]]},"references-count":87,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2024,7,16]]}},"alternative-id":["10.1161\/JAHA.123.034076"],"URL":"https:\/\/doi.org\/10.1161\/jaha.123.034076","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,16]]},"assertion":[{"value":"2024-02-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e034076"}}