{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T10:33:36Z","timestamp":1788518016340,"version":"build-2803163510"},"reference-count":62,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"682","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,2,8]]},"abstract":"<jats:p>\n                    Preservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization. Here, we showed that metabolic reprogramming through up-regulation of the enzyme immune response gene 1 (IRG1) and its product itaconate improved heart function after prolonged preservation.\n                    <jats:italic>Irg1<\/jats:italic>\n                    transcript induction was achieved by adding the histone deacetylase (HDAC) inhibitor valproic acid (VPA) to a histidine-tryptophan-ketoglutarate solution used for donor heart preservation. VPA increased acetylated H3K27 occupancy at the\n                    <jats:italic>IRG1<\/jats:italic>\n                    enhancer and\n                    <jats:italic>IRG1<\/jats:italic>\n                    transcript expression in human donor hearts. IRG1 converts aconitate to itaconate, which has both anti-inflammatory and antioxidant properties. Accordingly, our studies showed that\n                    <jats:italic>Irg1<\/jats:italic>\n                    transcript up-regulation by VPA treatment increased nuclear translocation of nuclear factor erythroid 2\u2013related factor 2 (Nrf2) in mice, which was accompanied by increased antioxidant protein expression [hemeoxygenase 1 (HO1) and superoxide dismutase 1 (SOD1)]. Deletion of\n                    <jats:italic>Irg1<\/jats:italic>\n                    in mice (Irg1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) negated the antioxidant and cardioprotective effects of VPA. Consistent with itaconate\u2019s ability to inhibit succinate dehydrogenase, VPA treatment of human hearts increased itaconate availability and reduced succinate accumulation during preservation. VPA similarly increased\n                    <jats:italic>IRG1<\/jats:italic>\n                    expression in pig donor hearts and improved its function in an ex vivo cardiac perfusion system both at the clinical 4-hour preservation threshold and at 10 hours. These results suggest that augmentation of cardioprotective immune-metabolomic pathways may be a promising therapeutic strategy for improving donor heart function in transplantation.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.ade3782","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T13:59:09Z","timestamp":1675864749000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":47,"title":["Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0248-6871","authenticated-orcid":true,"given":"Ienglam","family":"Lei","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6600-1258","authenticated-orcid":true,"given":"Pierre Emmanuel","family":"Noly","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Quebec H1T 1C8, Canada."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suyash","family":"Naik","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3876-4738","authenticated-orcid":true,"given":"Miriyam","family":"Ghali","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4430-9969","authenticated-orcid":true,"given":"Francis D.","family":"Pagani","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3057-6257","authenticated-orcid":true,"given":"Ashraf","family":"Abou El Ela","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5990-1071","authenticated-orcid":true,"given":"Jordan S.","family":"Pober","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University, New Haven, CT 06510, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertram","family":"Pitt","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey L.","family":"Platt","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilia","family":"Cascalho","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2357-7825","authenticated-orcid":true,"given":"Y. Eugene","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3625-7185","authenticated-orcid":true,"given":"Richard M.","family":"Mortensen","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Integrative Physiology, Internal Medicine, and Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-8587","authenticated-orcid":true,"given":"Paul C.","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, University of Michigan, Ann Arbor, MI 48109, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.117.004873"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.115.002679"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10741-019-09794-1"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/icvts\/ivu432"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.14588"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2019.01.088"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17060958"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-019-0115-y"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13909"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1402513"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-394309-5.00006-7"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2013.93"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2485"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2013.5776"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000319"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00577-x"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0802-2"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaw1026"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2013.01.038"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI69738"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210204"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.532"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics10040283"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2010.06.046"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0099-5428(05)32008-9"},{"key":"e_1_3_3_27_2","first-page":"Iii352","article-title":"Elevated tumor necrosis factor-\u03b1 and interleukin-6 in myocardium and serum of malfunctioning donor hearts","volume":"102","author":"Birks E. 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