{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T16:27:49Z","timestamp":1771259269797,"version":"3.50.1"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec>\n            <jats:title>Background.<\/jats:title>\n            <jats:p>Ischemia-reperfusion injury (IRI) is the major cause of primary graft dysfunction in organ transplantation. The mitogen-activated protein kinase\/extracellular signal-regulated kinase (ERK) signaling pathway plays a crucial role in cell physiological and pathological processes including IRI. This study aims to investigate whether inhibition of ERK signaling with U0126 can prevent prolonged cold IRI in heart transplantation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods.<\/jats:title>\n            <jats:p>Rat cardiac cell line H9c2 cells were treated with U0126 before exposure to hypothermic hypoxia\/reoxygenation (H\/R) conditions. The effect of U0126 on H9c2 cells in response to H\/R stress was determined by measuring cell death, reactive oxygen species production, mitochondrial membrane potential, and ERK signaling activation. Mouse syngeneic heterotopic heart transplantation was conducted, where a donor heart was preserved in the University of Wisconsin (UW) solution supplemented with U0126 for 24 hours at 4\u00b0C before transplantation. Heart graft function, histopathologic changes, apoptosis, and fibrosis were measured to assess IRI.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results.<\/jats:title>\n            <jats:p>Phosphorylated ERK was increased in both in vitro H\/R-injured H9c2 cells and in vivo heart grafts with IRI. Pretreatment with U0126 inhibited ERK phosphorylation and prevented H9c2 cells from cell death, reactive oxygen species generation, and mitochondrial membrane potential loss in response to H\/R. Preservation of donor hearts with U0126-supplemented solution improved graft function and reduced IRI by reductions in cell apoptosis\/death, neutrophil infiltration, and fibrosis of the graft.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions.<\/jats:title>\n            <jats:p>Addition of U0126 to UW solution reduces ERK signal activation and attenuates prolonged cold IRI in a heart transplantation model. ERK inhibition with U0126 may be a useful strategy to minimize IRI in organ transplantation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1097\/tp.0000000000003402","type":"journal-article","created":{"date-parts":[[2020,8,8]],"date-time":"2020-08-08T07:03:23Z","timestamp":1596870203000},"page":"308-317","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":14,"title":["An Addition of U0126 Protecting Heart Grafts From Prolonged Cold Ischemia-Reperfusion Injury in Heart Transplantation: A New Preservation Strategy"],"prefix":"10.1097","volume":"105","author":[{"given":"Hao","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada."},{"name":"College of Life Science, Wuhan University, Wuhan, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yale","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada."},{"name":"Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cuilin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada."},{"name":"Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas","family":"Quan","sequence":"additional","affiliation":[{"name":"Department of Surgery, Western University, London, ON, Canada."},{"name":"Department of Surgery, London Health Sciences Centre, London, ON, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anton I.","family":"Skaro","sequence":"additional","affiliation":[{"name":"Department of Surgery, Western University, London, ON, Canada."},{"name":"Department of Surgery, London Health Sciences Centre, London, ON, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vivian","family":"McAlister","sequence":"additional","affiliation":[{"name":"Department of Surgery, Western University, London, ON, Canada."},{"name":"Department of Surgery, London Health Sciences Centre, London, ON, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James C.","family":"Lacefield","sequence":"additional","affiliation":[{"name":"Department of Electrical and Computer Engineering, Western University, London, ON, Canada."},{"name":"Department of Medical Biophysics, Western University, London, ON, Canada."},{"name":"Department of Oncology, Western University, London, ON, Canada."},{"name":"Lawson Health Research Institute, London, ON, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jifu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Surgery, London Health Sciences Centre, London, ON, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Xue","sequence":"additional","affiliation":[{"name":"College of Life Science, Wuhan University, Wuhan, China."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yefu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiufen","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada."},{"name":"Department of Surgery, Western University, London, ON, Canada."},{"name":"Department of Surgery, London Health Sciences Centre, London, ON, Canada."},{"name":"Department of Oncology, Western University, London, ON, Canada."},{"name":"Lawson Health Research Institute, London, ON, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2020,7,27]]},"reference":[{"key":"R1-20250604","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1097\/TP.0000000000000072","article-title":"Mechanisms and consequences of injury and repair in older organ transplants.","volume":"97","author":"Slegtenhorst","year":"2014","journal-title":"Transplantation"},{"key":"R2-20250604","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1097\/TP.0b013e318295ee32","article-title":"Ischemia-reperfusion injury accelerates human antibody-mediated transplant vasculopathy.","volume":"96","author":"Goto","year":"2013","journal-title":"Transplantation"},{"key":"R3-20250604","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1161\/CIRCULATIONAHA.110.005249","article-title":"Donor simvastatin treatment abolishes rat cardiac allograft ischemia\/reperfusion injury and chronic rejection through microvascular protection.","volume":"124","author":"Tuuminen","year":"2011","journal-title":"Circulation"},{"key":"R4-20250604","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1016\/j.coi.2004.08.001","article-title":"Toll-like receptors and other links between innate and acquired alloimmunity.","volume":"16","author":"Goldstein","year":"2004","journal-title":"Curr Opin Immunol"},{"key":"R5-20250604","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.healun.2017.07.019","article-title":"The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Heart Transplantation Report-2017; Focus Theme: allograft ischemic time.","volume":"36","author":"Lund","year":"2017","journal-title":"J Heart Lung Transplant"},{"key":"R6-20250604","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","article-title":"Cell biology of ischemia\/reperfusion injury.","volume":"298","author":"Kalogeris","year":"2012","journal-title":"Int Rev Cell Mol Biol"},{"key":"R7-20250604","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1097\/TP.0000000000000960","article-title":"Attenuating ischemia-reperfusion injury in kidney transplantation by perfusing donor organs with siRNA cocktail solution.","volume":"100","author":"Zheng","year":"2016","journal-title":"Transplantation"},{"key":"R8-20250604","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1742-4658.2009.07366.x","article-title":"ERK and cell death: mechanisms of ERK-induced cell death\u2013apoptosis, autophagy and senescence.","volume":"277","author":"Cagnol","year":"2010","journal-title":"FEBS J"},{"key":"R9-20250604","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/ncb1757","article-title":"IQGAP3 regulates cell proliferation through the Ras\/ERK signalling cascade.","volume":"10","author":"Nojima","year":"2008","journal-title":"Nat Cell Biol"},{"key":"R10-20250604","doi-asserted-by":"crossref","first-page":"E955","DOI":"10.1210\/jc.2015-1431","article-title":"Up-regulation of Bcl-2 by CD147 through ERK activation results in abnormal cell survival in human endometriosis.","volume":"100","author":"Wang","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"R11-20250604","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s12031-015-0622-6","article-title":"The interplay of Akt and ERK in A\u03b2 toxicity and insulin-mediated protection in primary hippocampal cell culture.","volume":"57","author":"Ghasemi","year":"2015","journal-title":"J Mol Neurosci"},{"key":"R12-20250604","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainresbull.2017.10.015","article-title":"The anticonvulsant activity and cerebral protection of chronic lithium chloride via NMDA receptor\/nitric oxide and phospho-ERK.","volume":"137","author":"Mohammad Jafari","year":"2018","journal-title":"Brain Res Bull"},{"key":"R13-20250604","doi-asserted-by":"crossref","first-page":"1963","DOI":"10.1007\/s11064-018-2618-4","article-title":"NR4A1 Promotes cerebral ischemia reperfusion injury by repressing Mfn2-mediated mitophagy and inactivating the MAPK-ERK-CREB signaling pathway.","volume":"43","author":"Zhang","year":"2018","journal-title":"Neurochem Res"},{"key":"R14-20250604","doi-asserted-by":"crossref","first-page":"11569","DOI":"10.1073\/pnas.181213498","article-title":"Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia.","volume":"98","author":"Namura","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R15-20250604","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1161\/CIRCULATIONAHA.118.039262","article-title":"S100a8\/a9 signaling causes mitochondrial dysfunction and cardiomyocyte death in response to ischemic\/reperfusion injury.","volume":"140","author":"Li","year":"2019","journal-title":"Circulation"},{"key":"R16-20250604","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/01.TP.0000040429.40245.3A","article-title":"Effects of inhibition of myocardial extracellular-responsive kinase and P38 mitogen-activated protein kinase on mechanical function of rat hearts after prolonged hypothermic ischemia.","volume":"75","author":"Clanachan","year":"2003","journal-title":"Transplantation"},{"key":"R17-20250604","doi-asserted-by":"crossref","first-page":"36531","DOI":"10.18632\/oncotarget.16607","article-title":"Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I\/R) injury in heart transplantation through Foxo3a signaling.","volume":"8","author":"Zhang","year":"2017","journal-title":"Oncotarget"},{"key":"R18-20250604","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.1111\/ajt.15539","article-title":"Supplementing preservation solution with mitochondria-targeted H2 S donor AP39 protects cardiac grafts from prolonged cold ischemia-reperfusion injury in heart transplantation.","volume":"19","author":"Zhu","year":"2019","journal-title":"Am J Transplant"},{"key":"R19-20250604","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis.","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat Methods"},{"key":"R20-20250604","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1161\/CIRCULATIONAHA.108.787390","article-title":"Novel small interfering RNA-containing solution protecting donor organs in heart transplantation.","volume":"120","author":"Zheng","year":"2009","journal-title":"Circulation"},{"key":"R21-20250604","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/0002-9149(76)90491-4","article-title":"Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy.","volume":"37","author":"Teichholz","year":"1976","journal-title":"Am J Cardiol"},{"key":"R22-20250604","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1161\/CIRCULATIONAHA.117.029753","article-title":"Honoring 50 years of clinical heart transplantation in circulation: in-depth state-of-the-art review.","volume":"137","author":"Stehlik","year":"2018","journal-title":"Circulation"},{"key":"R23-20250604","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/00007890-200301150-00004","article-title":"Preconditioning with cyclosporine A or FK506 differentially regulates mitogen-activated protein kinase expression in rat kidneys with ischemia\/reperfusion injury.","volume":"75","author":"Yang","year":"2003","journal-title":"Transplantation"},{"key":"R24-20250604","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1097\/TP.0000000000002849","article-title":"Oligonucleotide-based preconditioning of DCD cardiac donors and its impact on cardiac viability.","volume":"103","author":"Kearns","year":"2019","journal-title":"Transplantation"},{"key":"R25-20250604","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1097\/TP.0000000000000926","article-title":"Cold crystalloid perfusion provides cardiac preservation superior to cold storage for donation after circulatory death.","volume":"100","author":"Choong","year":"2016","journal-title":"Transplantation"},{"key":"R26-20250604","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1097\/TP.0000000000001351","article-title":"The impact of total ischemic time, donor age and the pathway of donor death on graft outcomes after deceased donor kidney transplantation.","volume":"101","author":"Wong","year":"2017","journal-title":"Transplantation"},{"key":"R27-20250604","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1097\/TP.0b013e318190007d","article-title":"Life-years gained by reducing donor heart ischemic times.","volume":"87","author":"Goldsmith","year":"2009","journal-title":"Transplantation"},{"key":"R28-20250604","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1097\/TP.0000000000002629","article-title":"Cyclosporine A as a cardioprotective agent during donor heart retrieval, storage, or transportation: benefits and limitations.","volume":"103","author":"Gao","year":"2019","journal-title":"Transplantation"},{"key":"R29-20250604","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1097\/TP.0b013e3182115b4b","article-title":"A recombinant human neuregulin-1 peptide improves preservation of the rodent heart after prolonged hypothermic storage.","volume":"91","author":"Jabbour","year":"2011","journal-title":"Transplantation"},{"key":"R30-20250604","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1161\/01.RES.86.6.692","article-title":"Inhibition of extracellular signal-regulated kinase enhances ischemia\/reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart.","volume":"86","author":"Yue","year":"2000","journal-title":"Circ Res"},{"key":"R31-20250604","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3892\/ijmm.2015.2402","article-title":"Osthole ameliorates acute myocardial infarction in rats by decreasing the expression of inflammatory-related cytokines, diminishing MMP-2 expression and activating p-ERK.","volume":"37","author":"Duan","year":"2016","journal-title":"Int J Mol Med"},{"key":"R32-20250604","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.ejphar.2016.06.038","article-title":"U0126 attenuates ischemia\/reperfusion-induced apoptosis and autophagy in myocardium through MEK\/ERK\/EGR-1 pathway.","volume":"788","author":"Wang","year":"2016","journal-title":"Eur J Pharmacol"},{"key":"R33-20250604","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.3389\/fphys.2019.01038","article-title":"Role of the extracellular signal-regulated kinase \u00bd signaling pathway in ischemia-reperfusion injury.","volume":"10","author":"Kong","year":"2019","journal-title":"Front Physiol"},{"key":"R34-20250604","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1161\/01.CIR.0000127126.73759.23","article-title":"MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo.","volume":"109","author":"Lips","year":"2004","journal-title":"Circulation"},{"key":"R35-20250604","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.ejphar.2016.11.053","article-title":"Role of carvacrol in cardioprotection against myocardial ischemia\/reperfusion injury in rats through activation of MAPK\/ERK and Akt\/eNOS signaling pathways.","volume":"796","author":"Chen","year":"2017","journal-title":"Eur J Pharmacol"},{"key":"R36-20250604","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1097\/TP.0b013e318160130f","article-title":"Blockade of p38 MAPK inhibits chronic allograft vasculopathy.","volume":"85","author":"Ollinger","year":"2008","journal-title":"Transplantation"},{"key":"R37-20250604","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1097\/00005344-200008000-00012","article-title":"Inhibition of the ER-kinase cascade by PD98059 and UO126 counteracts ischemic preconditioning in pig myocardium.","volume":"36","author":"Strohm","year":"2000","journal-title":"J Cardiovasc Pharmacol"},{"key":"R38-20250604","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1007\/s10495-006-6305-6","article-title":"Role of ERK1\/2 in the anti-apoptotic and cardioprotective effects of nitric oxide after myocardial ischemia and reperfusion.","volume":"11","author":"Li","year":"2006","journal-title":"Apoptosis"},{"key":"R39-20250604","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.metabol.2015.10.022","article-title":"The protective effect of trimetazidine on myocardial ischemia\/reperfusion injury through activating AMPK and ERK signaling pathway.","volume":"65","author":"Liu","year":"2016","journal-title":"Metabolism"},{"key":"R40-20250604","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s00395-011-0165-0","article-title":"Cardioprotection by mild hypothermia during ischemia involves preservation of ERK activity.","volume":"106","author":"Yang","year":"2011","journal-title":"Basic Res Cardiol"},{"key":"R41-20250604","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1089\/hum.2006.17.1201","article-title":"Novel role of kallistatin in protection against myocardial ischemia-reperfusion injury by preventing apoptosis and inflammation.","volume":"17","author":"Chao","year":"2006","journal-title":"Hum Gene Ther"},{"key":"R42-20250604","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.chemphyslip.2016.04.007","article-title":"High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms.","volume":"199","author":"White","year":"2016","journal-title":"Chem Phys Lipids"},{"key":"R43-20250604","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12860-016-0100-1","article-title":"Microvesicles derived from hypoxia\/reoxygenation-treated human umbilical vein endothelial cells promote apoptosis and oxidative stress in H9c2 cardiomyocytes.","volume":"17","author":"Zhang","year":"2016","journal-title":"BMC Cell Biol"},{"key":"R44-20250604","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1142\/S0192415X13500237","article-title":"Baicalein preconditioning protects cardiomyocytes from ischemia-reperfusion injury via mitochondrial oxidant signaling.","volume":"41","author":"Chang","year":"2013","journal-title":"Am J Chin Med"},{"key":"R45-20250604","doi-asserted-by":"crossref","first-page":"18623","DOI":"10.1074\/jbc.273.29.18623","article-title":"Identification of a novel inhibitor of mitogen-activated protein kinase kinase.","volume":"273","author":"Favata","year":"1998","journal-title":"J Biol Chem"},{"key":"R46-20250604","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/1465-9921-6-36","article-title":"Inhibitors of mitogen-activated protein kinases differentially regulate costimulated T cell cytokine production and mouse airway eosinophilia.","volume":"6","author":"Chialda","year":"2005","journal-title":"Respir Res"},{"key":"R47-20250604","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1097\/01.tp.0000251374.49225.19","article-title":"Prolongation of cardiac allograft survival by inhibition of ERK1\/2 signaling in a mouse model.","volume":"83","author":"Wang","year":"2007","journal-title":"Transplantation"}],"container-title":["Transplantation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.lww.com\/10.1097\/TP.0000000000003402","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T19:02:30Z","timestamp":1749063750000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1097\/TP.0000000000003402"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,27]]},"references-count":47,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1097\/tp.0000000000003402","relation":{},"ISSN":["0041-1337"],"issn-type":[{"value":"0041-1337","type":"print"}],"subject":[],"published":{"date-parts":[[2020,7,27]]}}}