{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T03:55:24Z","timestamp":1792295724602,"version":"4.4.0"},"reference-count":53,"publisher":"American Society for Clinical Investigation","issue":"20","license":[{"start":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T00:00:00Z","timestamp":1729555200000},"content-version":"vor","delay-in-days":28,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01HL133951"],"award-info":[{"award-number":["R01HL133951"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01HL140409"],"award-info":[{"award-number":["R01HL140409"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01HL148810"],"award-info":[{"award-number":["R01HL148810"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01HL164014"],"award-info":[{"award-number":["R01HL164014"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01HL162299"],"award-info":[{"award-number":["R01HL162299"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000050","name":"NHLBI","doi-asserted-by":"crossref","award":["R01HL172447"],"award-info":[{"award-number":["R01HL172447"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"crossref","award":["19PRE34450171"],"award-info":[{"award-number":["19PRE34450171"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,10,22]]},"abstract":"<jats:p>\n                    Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and remodeling that result in right heart failure. Recessive mutations of\n                    <jats:italic>EIF2AK4<\/jats:italic>\n                    gene (encoding general control nonderepressible 2 kinase, GCN2) are linked to heritable pulmonary veno-occlusive disease (PVOD) in patients but rarely in patients with PAH. The role of GCN2 kinase activation in the pathogenesis of PAH remains unclear. Here, we show that GCN2 was hyperphosphorylated and activated in pulmonary vascular endothelial cells (ECs) of hypoxic mice, monocrotaline-treated rats, and patients with idiopathic PAH. Unexpectedly, loss of GCN2 kinase activity in\n                    <jats:italic>\n                      Eif2ak4\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice with genetic disruption of the kinase domain induced neither PVOD nor pulmonary hypertension (PH) but inhibited hypoxia-induced PH. RNA-sequencing analysis suggested endothelin-1 (Edn1) as a downstream target of GCN2. GCN2 mediated hypoxia-induced Edn1 expression in human lung ECs via HIF-2\u03b1. Restored Edn1 expression in ECs of\n                    <jats:italic>\n                      Eif2ak4\n                      <jats:sup>\u2013\/\u2013<\/jats:sup>\n                    <\/jats:italic>\n                    mice partially reversed the reduced phenotype of hypoxia-induced PH. Furthermore, GCN2 kinase inhibitor A-92 treatment attenuated PAH in monocrotaline-treated rats. These studies demonstrate that GCN2 kinase activation mediates pulmonary vascular remodeling and PAH at least partially through Edn1. Thus, targeting GCN2 kinase activation is a promising therapeutic strategy for treatment of PAH in patients without\n                    <jats:italic>EIF2AK4<\/jats:italic>\n                    loss-of-function mutations.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.177926","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T12:00:27Z","timestamp":1727179227000},"source":"Crossref","is-referenced-by-count":15,"title":["GCN2 kinase activation mediates pulmonary vascular remodeling and pulmonary arterial hypertension"],"prefix":"10.1172","volume":"9","author":[{"given":"Maggie M.","family":"Zhu","sequence":"first","affiliation":[{"name":"Program for Lung and Vascular Biology, Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, Illinois, USA."},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingbo","family":"Dai","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, Illinois, USA."},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-7923","authenticated-orcid":true,"given":"Zhiyu","family":"Dai","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, Illinois, USA."},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Peng","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, Illinois, USA."},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-0339","authenticated-orcid":true,"given":"You-Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology, Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, Illinois, USA."},{"name":"Department of Pediatrics, Division of Critical Care, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."},{"name":"Genetic Medicine and Nanotechnology Development Center (GeneMeNDer), Stanley Manne Children\u2019s Research Institute, Ann & Robert H. Lurie Children\u2019s Hospital of Chicago, Chicago, Illinois, USA."},{"name":"Departments of Pharmacology and Medicine and"},{"name":"Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2024,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/suz211"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00543-3"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra040291"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.192230"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv317"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-115-5-343"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1413687"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1378\/chest.11-1460"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.02043-2015"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.06.068"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2017.84"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1999.00780.x"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/154.2.787"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)00108-8"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.8.2706-2717.2000"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.13.8.5099-5111.1993"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)00028-9"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1126\/science.2047877"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.8.4497"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.5.2697"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.6.1425"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.4.2282"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.12.12.5700-5710.1992"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504096200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1101\/gad.979402"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)01037-0"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.104.031443"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1593\/neo.91354"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0408-0"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/nature17186"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2844"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00090608"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.028351"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-016-0457-x"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110196"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e05-03-0268"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.01.133"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.02.002"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20101732"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115367"},{"issue":"3","key":"B41","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/S0022-3565(24)36925-3","article-title":"The orally active ET(A) receptor antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphe nyl-propionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated rats","volume":"282","author":"Prie","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2015.08.002"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199306173282402"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M011344200"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007042729486"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1021\/ml500052f"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.19.6681-6688.2002"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0184-2020"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2017.09.022"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2019.05.019"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.03957-2020"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201709-1835OC"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.021494"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/177926\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T20:38:35Z","timestamp":1779136715000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/177926"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,24]]},"references-count":53,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10,22]]},"published-print":{"date-parts":[[2024,10,22]]}},"alternative-id":["10.1172\/jci.insight.177926"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.177926","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,24]]},"article-number":"e177926"}}