{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T03:19:28Z","timestamp":1785295168116,"version":"3.55.0"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T00:00:00Z","timestamp":1656633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL136438"],"award-info":[{"award-number":["R01HL136438"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL061483"],"award-info":[{"award-number":["R01HL061483"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01HL051971"],"award-info":[{"award-number":["P01HL051971"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM104357"],"award-info":[{"award-number":["P20GM104357"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103476"],"award-info":[{"award-number":["P20GM103476"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM103328"],"award-info":[{"award-number":["P30GM103328"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006518","name":"University of Nebraska Medical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006518","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Basic Res Cardiol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Transcription factors play a fundamental role in cardiovascular adaptation to stress. Nuclear receptor subfamily 4 group A member 2 (NR4A2; NURR1) is an immediate-early gene and transcription factor with a versatile role throughout many organs. In the adult mammalian heart, and particularly in cardiac myocytes, NR4A2 is strongly up-regulated in response to beta-adrenergic stimulation. The physiologic implications of this increase remain unknown. In this study, we aimed to interrogate the consequences of cardiac NR4A2 up-regulation under normal conditions and in response to pressure overload. In mice, tamoxifen-dependent, cardiomyocyte-restricted overexpression of NR4A2 led to cardiomyocyte hypertrophy, left ventricular dilation, heart failure, and death within 40\u00a0days. Chronic NR4A2 induction also precipitated cardiac decompensation during transverse aortic constriction (TAC)-induced pressure overload. Mechanistically, NR4A2 caused adult cardiac myocytes to return to a fetal-like phenotype, with a switch to glycolytic metabolism and disassembly of sarcomeric structures. NR4A2 also re-activated cell cycle progression and stimulated DNA replication and karyokinesis but failed to induce cytokinesis, thereby promoting multinucleation of cardiac myocytes. Activation of cell cycle checkpoints led to induction of an apoptotic response which ultimately resulted in excessive loss of cardiac myocytes and impaired left ventricular contractile function. In summary, myocyte-specific overexpression of NR4A2 in the postnatal mammalian heart results in increased cell cycle re-entry and DNA replication but does not result in cardiac myocyte division. Our findings expose a novel function for the nuclear receptor as a critical regulator in the self-renewal of the cardiac myocyte and heart regeneration.<\/jats:p>","DOI":"10.1007\/s00395-022-00942-7","type":"journal-article","created":{"date-parts":[[2022,7,1]],"date-time":"2022-07-01T10:13:38Z","timestamp":1656670418000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Prolonged cardiac NR4A2 activation causes dilated cardiomyopathy in mice"],"prefix":"10.1007","volume":"117","author":[{"given":"Sadia","family":"Ashraf","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinrich","family":"Taegtmeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5040-4500","authenticated-orcid":false,"given":"Romain","family":"Harmancey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,1]]},"reference":[{"key":"942_CR1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1111\/febs.15146","volume":"287","author":"H Ali","year":"2020","unstructured":"Ali H, Braga L, Giacca M (2020) Cardiac regeneration and remodelling of the cardiomyocyte cytoarchitecture. FEBS J 287:417\u2013438. https:\/\/doi.org\/10.1111\/febs.15146","journal-title":"FEBS J"},{"key":"942_CR2","doi-asserted-by":"publisher","first-page":"11299","DOI":"10.1073\/pnas.1902490116","volume":"116","author":"L Amoasii","year":"2019","unstructured":"Amoasii L, Sanchez-Ortiz E, Fujikawa T, Elmquist JK, Bassel-Duby R, Olson EN (2019) NURR1 activation in skeletal muscle controls systemic energy homeostasis. Proc Natl Acad Sci USA 116:11299\u201311308. https:\/\/doi.org\/10.1073\/pnas.1902490116","journal-title":"Proc Natl Acad Sci USA"},{"key":"942_CR3","doi-asserted-by":"publisher","first-page":"C513","DOI":"10.1152\/ajpcell.00526.2018","volume":"317","author":"S Ashraf","year":"2019","unstructured":"Ashraf S, Hegazy YK, Harmancey R (2019) Nuclear receptor subfamily 4 group A member 2 inhibits activation of ERK signaling and cell growth in response to beta-adrenergic stimulation in adult rat cardiomyocytes. Am J Physiol Cell Physiol 317:C513\u2013C524. https:\/\/doi.org\/10.1152\/ajpcell.00526.2018","journal-title":"Am J Physiol Cell Physiol"},{"key":"942_CR4","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1161\/hc3101.093903","volume":"104","author":"A Barbone","year":"2001","unstructured":"Barbone A, Holmes JW, Heerdt PM, The AH, Naka Y, Joshi N, Daines M, Marks AR, Oz MC, Burkhoff D (2001) Comparison of right and left ventricular responses to left ventricular assist device support in patients with severe heart failure: a primary role of mechanical unloading underlying reverse remodeling. Circulation 104:670\u2013675. https:\/\/doi.org\/10.1161\/hc3101.093903","journal-title":"Circulation"},{"key":"942_CR5","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nature22978","volume":"547","author":"E Bassat","year":"2017","unstructured":"Bassat E, Mutlak YE, Genzelinakh A, Shadrin IY, Baruch Umansky K, Yifa O, Kain D, Rajchman D, Leach J, Riabov Bassat D, Udi Y, Sarig R, Sagi I, Martin JF, Bursac N, Cohen S, Tzahor E (2017) The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 547:179\u2013184. https:\/\/doi.org\/10.1038\/nature22978","journal-title":"Nature"},{"key":"942_CR6","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9091233","author":"PC Berg","year":"2021","unstructured":"Berg PC, Hansson AML, Rosand O, Marwarha G, Hoydal MA (2021) Overexpression of neuron-derived orphan receptor 1 (NOR-1) rescues cardiomyocytes from cell death and improves viability after doxorubicin induced stress. Biomedicines. https:\/\/doi.org\/10.3390\/biomedicines9091233","journal-title":"Biomedicines"},{"key":"942_CR7","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/s42255-020-0169-x","volume":"2","author":"AC Cardoso","year":"2020","unstructured":"Cardoso AC, Lam NT, Savla JJ, Nakada Y, Pereira AHM, Elnwasany A, Menendez-Montes I, Ensley EL, Petric UB, Sharma G, Sherry AD, Malloy CR, Khemtong C, Kinter MT, Tan WLW, Anene-Nzelu CG, Foo RS, Nguyen NUN, Li S, Ahmed MS, Elhelaly WM, Abdisalaam S, Asaithamby A, Xing C, Kanchwala M, Vale G, Eckert KM, Mitsche MA, McDonald JG, Hill JA, Huang L, Shaul PW, Szweda LI, Sadek HA (2020) Mitochondrial substrate utilization regulates cardiomyocyte cell cycle progression. Nat Metab 2:167\u2013178","journal-title":"Nat Metab"},{"key":"942_CR8","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/j.humpath.2009.12.008","volume":"41","author":"KT Chang","year":"2010","unstructured":"Chang KT, Taylor GP, Meschino WS, Kantor PF, Cutz E (2010) Mitogenic cardiomyopathy: a lethal neonatal familial dilated cardiomyopathy characterized by myocyte hyperplasia and proliferation. Hum Pathol 41:1002\u20131008. https:\/\/doi.org\/10.1016\/j.humpath.2009.12.008","journal-title":"Hum Pathol"},{"key":"942_CR9","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.yjmcc.2021.05.016","volume":"158","author":"GE Davogustto","year":"2021","unstructured":"Davogustto GE, Salazar RL, Vasquez HG, Karlstaedt A, Dillon WP, Guthrie PH, Martin JR, Vitrac H, De La Guardia G, Vela D, Ribas-Latre A, Baumgartner C, Eckel-Mahan K, Taegtmeyer H (2021) Metabolic remodeling precedes mTORC1-mediated cardiac hypertrophy. J Mol Cell Cardiol 158:115\u2013127. https:\/\/doi.org\/10.1016\/j.yjmcc.2021.05.016","journal-title":"J Mol Cell Cardiol"},{"key":"942_CR10","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1038\/3253","volume":"4","author":"C Depre","year":"1998","unstructured":"Depre C, Shipley GL, Chen W, Han Q, Doenst T, Moore ML, Stepkowski S, Davies PJ, Taegtmeyer H (1998) Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat Med 4:1269\u20131275. https:\/\/doi.org\/10.1038\/3253","journal-title":"Nat Med"},{"key":"942_CR11","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1016\/j.yjmcc.2006.06.012","volume":"41","author":"FB Engel","year":"2006","unstructured":"Engel FB, Schebesta M, Keating MT (2006) Anillin localization defect in cardiomyocyte binucleation. J Mol Cell Cardiol 41:601\u2013612. https:\/\/doi.org\/10.1016\/j.yjmcc.2006.06.012","journal-title":"J Mol Cell Cardiol"},{"key":"942_CR12","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1056\/NEJM200004133421502","volume":"342","author":"GM Felker","year":"2000","unstructured":"Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, Baughman KL, Kasper EK (2000) Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med 342:1077\u20131084. https:\/\/doi.org\/10.1056\/NEJM200004133421502","journal-title":"N Engl J Med"},{"key":"942_CR13","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201949752","volume":"21","author":"R Fukuda","year":"2020","unstructured":"Fukuda R, Marin-Juez R, El-Sammak H, Beisaw A, Ramadass R, Kuenne C, Guenther S, Konzer A, Bhagwat AM, Graumann J, Stainier DY (2020) Stimulation of glycolysis promotes cardiomyocyte proliferation after injury in adult zebrafish. EMBO Rep 21:e49752. https:\/\/doi.org\/10.15252\/embr.201949752","journal-title":"EMBO Rep"},{"key":"942_CR14","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/s41392-020-00413-2","volume":"6","author":"R Gong","year":"2021","unstructured":"Gong R, Jiang Z, Zagidullin N, Liu T, Cai B (2021) Regulation of cardiomyocyte fate plasticity: a key strategy for cardiac regeneration. Signal Transduct Target Ther 6:31. https:\/\/doi.org\/10.1038\/s41392-020-00413-2","journal-title":"Signal Transduct Target Ther"},{"key":"942_CR15","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.cr.2018.11.002","volume":"8","author":"S Hashmi","year":"2019","unstructured":"Hashmi S, Ahmad HR (2019) Molecular switch model for cardiomyocyte proliferation. Cell Regen 8:12\u201320. https:\/\/doi.org\/10.1016\/j.cr.2018.11.002","journal-title":"Cell Regen"},{"key":"942_CR16","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/s0008-6363(97)00140-5","volume":"36","author":"GW Herget","year":"1997","unstructured":"Herget GW, Neuburger M, Plagwitz R, Adler CP (1997) DNA content, ploidy level and number of nuclei in the human heart after myocardial infarction. Cardiovasc Res 36:45\u201351. https:\/\/doi.org\/10.1016\/s0008-6363(97)00140-5","journal-title":"Cardiovasc Res"},{"key":"942_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/cells8111373","author":"JA Herring","year":"2019","unstructured":"Herring JA, Elison WS, Tessem JS (2019) Function of Nr4a orphan nuclear receptors in proliferation, apoptosis and fuel utilization across tissues. Cells. https:\/\/doi.org\/10.3390\/cells8111373","journal-title":"Cells"},{"key":"942_CR18","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1161\/CIRCRESAHA.118.312792","volume":"123","author":"M Hesse","year":"2018","unstructured":"Hesse M, Doengi M, Becker A, Kimura K, Voeltz N, Stein V, Fleischmann BK (2018) Midbody positioning and distance between daughter nuclei enable unequivocal identification of cardiomyocyte cell division in mice. Circ Res 123:1039\u20131052. https:\/\/doi.org\/10.1161\/CIRCRESAHA.118.312792","journal-title":"Circ Res"},{"key":"942_CR19","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.bbrc.2019.07.116","volume":"517","author":"Y Jiang","year":"2019","unstructured":"Jiang Y, Feng YP, Tang LX, Yan YL, Bai JW (2019) The protective role of NR4A3 in acute myocardial infarction by suppressing inflammatory responses via JAK2-STAT3\/NF-kappaB pathway. Biochem Biophys Res Commun 517:697\u2013702. https:\/\/doi.org\/10.1016\/j.bbrc.2019.07.116","journal-title":"Biochem Biophys Res Commun"},{"key":"942_CR20","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.yjmcc.2019.11.155","volume":"138","author":"YH Jiang","year":"2020","unstructured":"Jiang YH, Wang HL, Peng J, Zhu Y, Zhang HG, Tang FQ, Jian Z, Xiao YB (2020) Multinucleated polyploid cardiomyocytes undergo an enhanced adaptability to hypoxia via mitophagy. J Mol Cell Cardiol 138:115\u2013135. https:\/\/doi.org\/10.1016\/j.yjmcc.2019.11.155","journal-title":"J Mol Cell Cardiol"},{"key":"942_CR21","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1038\/nature08899","volume":"464","author":"C Jopling","year":"2010","unstructured":"Jopling C, Sleep E, Raya M, Marti M, Raya A, Izpisua Belmonte JC (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464:606\u2013609. https:\/\/doi.org\/10.1038\/nature08899","journal-title":"Nature"},{"key":"942_CR22","doi-asserted-by":"publisher","first-page":"71","DOI":"10.3858\/emm.2008.40.1.71","volume":"40","author":"BY Kim","year":"2008","unstructured":"Kim BY, Kim H, Cho EJ, Youn HD (2008) Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation. Exp Mol Med 40:71\u201383. https:\/\/doi.org\/10.3858\/emm.2008.40.1.71","journal-title":"Exp Mol Med"},{"key":"942_CR23","doi-asserted-by":"publisher","first-page":"8756","DOI":"10.1073\/pnas.1509742112","volume":"112","author":"CH Kim","year":"2015","unstructured":"Kim CH, Han BS, Moon J, Kim DJ, Shin J, Rajan S, Nguyen QT, Sohn M, Kim WG, Han M, Jeong I, Kim KS, Lee EH, Tu Y, Naffin-Olivos JL, Park CH, Ringe D, Yoon HS, Petsko GA, Kim KS (2015) Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson\u2019s disease. Proc Natl Acad Sci USA 112:8756\u20138761. https:\/\/doi.org\/10.1073\/pnas.1509742112","journal-title":"Proc Natl Acad Sci USA"},{"key":"942_CR24","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1038\/sj.emboj.7600196","volume":"23","author":"M Koshiji","year":"2004","unstructured":"Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE (2004) HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 23:1949\u20131956. https:\/\/doi.org\/10.1038\/sj.emboj.7600196","journal-title":"EMBO J"},{"key":"942_CR25","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1159\/000369782","volume":"130","author":"BK Kundu","year":"2015","unstructured":"Kundu BK, Zhong M, Sen S, Davogustto G, Keller SR, Taegtmeyer H (2015) Remodeling of glucose metabolism precedes pressure overload-induced left ventricular hypertrophy: review of a hypothesis. Cardiology 130:211\u2013220. https:\/\/doi.org\/10.1159\/000369782","journal-title":"Cardiology"},{"key":"942_CR26","doi-asserted-by":"publisher","first-page":"2543","DOI":"10.1016\/j.bbamcr.2014.06.010","volume":"1843","author":"K Kurakula","year":"2014","unstructured":"Kurakula K, Koenis DS, van Tiel CM, de Vries CJ (2014) NR4A nuclear receptors are orphans but not lonesome. Biochim Biophys Acta 1843:2543\u20132555. https:\/\/doi.org\/10.1016\/j.bbamcr.2014.06.010","journal-title":"Biochim Biophys Acta"},{"key":"942_CR27","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1101\/gad.1661708","volume":"22","author":"L Lai","year":"2008","unstructured":"Lai L, Leone TC, Zechner C, Schaeffer PJ, Kelly SM, Flanagan DP, Medeiros DM, Kovacs A, Kelly DP (2008) Transcriptional coactivators PGC-1alpha and PGC-lbeta control overlapping programs required for perinatal maturation of the heart. Genes Dev 22:1948\u20131961. https:\/\/doi.org\/10.1101\/gad.1661708","journal-title":"Genes Dev"},{"key":"942_CR28","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/s10974-019-09545-7","volume":"41","author":"M Landim-Vieira","year":"2020","unstructured":"Landim-Vieira M, Schipper JM, Pinto JR, Chase PB (2020) Cardiomyocyte nuclearity and ploidy: when is double trouble? J Muscle Res Cell Motil 41:329\u2013340. https:\/\/doi.org\/10.1007\/s10974-019-09545-7","journal-title":"J Muscle Res Cell Motil"},{"key":"942_CR29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007172","volume":"4","author":"HG Lee","year":"2009","unstructured":"Lee HG, Chen Q, Wolfram JA, Richardson SL, Liner A, Siedlak SL, Zhu X, Ziats NP, Fujioka H, Felsher DW, Castellani RJ, Valencik ML, McDonald JA, Hoit BD, Lesnefsky EJ, Smith MA (2009) Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure. PLoS ONE 4:e7172. https:\/\/doi.org\/10.1371\/journal.pone.0007172","journal-title":"PLoS ONE"},{"key":"942_CR30","doi-asserted-by":"publisher","first-page":"H733","DOI":"10.1152\/ajpheart.00339.2017","volume":"314","author":"ML Lindsey","year":"2018","unstructured":"Lindsey ML, Kassiri Z, Virag JAI, de Castro Bras LE, Scherrer-Crosbie M (2018) Guidelines for measuring cardiac physiology in mice. Am J Physiol Heart Circ Physiol 314:H733\u2013H752. https:\/\/doi.org\/10.1152\/ajpheart.00339.2017","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"942_CR31","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nrm3495","volume":"14","author":"M Maillet","year":"2013","unstructured":"Maillet M, van Berlo JH, Molkentin JD (2013) Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14:38\u201348. https:\/\/doi.org\/10.1038\/nrm3495","journal-title":"Nat Rev Mol Cell Biol"},{"key":"942_CR32","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1016\/j.tcm.2018.11.015","volume":"29","author":"L Medzikovic","year":"2019","unstructured":"Medzikovic L, de Vries CJM, de Waard V (2019) NR4A nuclear receptors in cardiac remodeling and neurohormonal regulation. Trends Cardiovasc Med 29:429\u2013437. https:\/\/doi.org\/10.1016\/j.tcm.2018.11.015","journal-title":"Trends Cardiovasc Med"},{"key":"942_CR33","doi-asserted-by":"publisher","first-page":"15404","DOI":"10.1038\/srep15404","volume":"5","author":"L Medzikovic","year":"2015","unstructured":"Medzikovic L, Schumacher CA, Verkerk AO, van Deel ED, Wolswinkel R, van der Made I, Bleeker N, Cakici D, van den Hoogenhof MM, Meggouh F, Creemers EE, Remme CA, Baartscheer A, de Winter RJ, de Vries CJ, Arkenbout EK, de Waard V (2015) Orphan nuclear receptor Nur77 affects cardiomyocyte calcium homeostasis and adverse cardiac remodelling. Sci Rep 5:15404. https:\/\/doi.org\/10.1038\/srep15404","journal-title":"Sci Rep"},{"key":"942_CR34","doi-asserted-by":"publisher","first-page":"1617","DOI":"10.1093\/cvr\/cvy125","volume":"114","author":"L Medzikovic","year":"2018","unstructured":"Medzikovic L, van Roomen C, Baartscheer A, van Loenen PB, de Vos J, Bakker E, Koenis DS, Damanafshan A, Creemers EE, Arkenbout EK, de Vries CJM, de Waard V (2018) Nur77 protects against adverse cardiac remodelling by limiting neuropeptide Y signalling in the sympathoadrenal-cardiac axis. Cardiovasc Res 114:1617\u20131628. https:\/\/doi.org\/10.1093\/cvr\/cvy125","journal-title":"Cardiovasc Res"},{"key":"942_CR35","doi-asserted-by":"publisher","first-page":"6998","DOI":"10.1073\/pnas.1920391117","volume":"117","author":"NK Mehta","year":"2020","unstructured":"Mehta NK, Abrams LR, Myrskyla M (2020) US life expectancy stalls due to cardiovascular disease, not drug deaths. Proc Natl Acad Sci USA 117:6998\u20137000. https:\/\/doi.org\/10.1073\/pnas.1920391117","journal-title":"Proc Natl Acad Sci USA"},{"key":"942_CR36","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.mce.2009.05.006","volume":"309","author":"SA Myers","year":"2009","unstructured":"Myers SA, Eriksson N, Burow R, Wang SC, Muscat GE (2009) Beta-adrenergic signaling regulates NR4A nuclear receptor and metabolic gene expression in multiple tissues. Mol Cell Endocrinol 309:101\u2013108. https:\/\/doi.org\/10.1016\/j.mce.2009.05.006","journal-title":"Mol Cell Endocrinol"},{"key":"942_CR37","doi-asserted-by":"publisher","first-page":"1457","DOI":"10.1172\/JCI18611","volume":"111","author":"B Nadal-Ginard","year":"2003","unstructured":"Nadal-Ginard B, Kajstura J, Anversa P, Leri A (2003) A matter of life and death: cardiac myocyte apoptosis and regeneration. J Clin Invest 111:1457\u20131459. https:\/\/doi.org\/10.1172\/JCI18611","journal-title":"J Clin Invest"},{"key":"942_CR38","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1038\/ncb2585","volume":"14","author":"SK Pandit","year":"2012","unstructured":"Pandit SK, Westendorp B, Nantasanti S, van Liere E, Tooten PC, Cornelissen PW, Toussaint MJ, Lamers WH, de Bruin A (2012) E2F8 is essential for polyploidization in mammalian cells. Nat Cell Biol 14:1181\u20131191. https:\/\/doi.org\/10.1038\/ncb2585","journal-title":"Nat Cell Biol"},{"key":"942_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.steroids.2014.12.020","volume":"95","author":"A Pawlak","year":"2015","unstructured":"Pawlak A, Strzadala L, Kalas W (2015) Non-genomic effects of the NR4A1\/Nur77\/TR3\/NGFIB orphan nuclear receptor. Steroids 95:1\u20136. https:\/\/doi.org\/10.1016\/j.steroids.2014.12.020","journal-title":"Steroids"},{"key":"942_CR40","doi-asserted-by":"publisher","first-page":"4264","DOI":"10.1038\/srep04264","volume":"4","author":"S Perez-Sieira","year":"2014","unstructured":"Perez-Sieira S, Lopez M, Nogueiras R, Tovar S (2014) Regulation of NR4A by nutritional status, gender, postnatal development and hormonal deficiency. Sci Rep 4:4264. https:\/\/doi.org\/10.1038\/srep04264","journal-title":"Sci Rep"},{"key":"942_CR41","doi-asserted-by":"publisher","first-page":"1850","DOI":"10.1093\/eurheartj\/ehv727","volume":"37","author":"YM Pinto","year":"2016","unstructured":"Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Bohm M, Duboc D, Gimeno J, de Groote P, Imazio M, Heymans S, Klingel K, Komajda M, Limongelli G, Linhart A, Mogensen J, Moon J, Pieper PG, Seferovic PM, Schueler S, Zamorano JL, Caforio AL, Charron P (2016) Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J 37:1850\u20131858. https:\/\/doi.org\/10.1093\/eurheartj\/ehv727","journal-title":"Eur Heart J"},{"key":"942_CR42","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.ppedcard.2011.02.002","volume":"31","author":"GA Porter Jr","year":"2011","unstructured":"Porter GA Jr, Hom J, Hoffman D, Quintanilla R, de Mesy BK, Sheu SS (2011) Bioenergetics, mitochondria, and cardiac myocyte differentiation. Prog Pediatr Cardiol 31:75\u201381. https:\/\/doi.org\/10.1016\/j.ppedcard.2011.02.002","journal-title":"Prog Pediatr Cardiol"},{"key":"942_CR43","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.cell.2014.03.032","volume":"157","author":"BN Puente","year":"2014","unstructured":"Puente BN, Kimura W, Muralidhar SA, Moon J, Amatruda JF, Phelps KL, Grinsfelder D, Rothermel BA, Chen R, Garcia JA, Santos CX, Thet S, Mori E, Kinter MT, Rindler PM, Zacchigna S, Mukherjee S, Chen DJ, Mahmoud AI, Giacca M, Rabinovitch PS, Aroumougame A, Shah AM, Szweda LI, Sadek HA (2014) The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 157:565\u2013579. https:\/\/doi.org\/10.1016\/j.cell.2014.03.032","journal-title":"Cell"},{"key":"942_CR44","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1038\/sj.mp.4001993","volume":"12","author":"P Rojas","year":"2007","unstructured":"Rojas P, Joodmardi E, Hong Y, Perlmann T, Ogren SO (2007) Adult mice with reduced Nurr1 expression: an animal model for schizophrenia. Mol Psychiatry 12:756\u2013766. https:\/\/doi.org\/10.1038\/sj.mp.4001993","journal-title":"Mol Psychiatry"},{"key":"942_CR45","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.jsbmb.2015.04.016","volume":"157","author":"S Safe","year":"2016","unstructured":"Safe S, Jin UH, Morpurgo B, Abudayyeh A, Singh M, Tjalkens RB (2016) Nuclear receptor 4A (NR4A) family - orphans no more. J Steroid Biochem Mol Biol 157:48\u201360. https:\/\/doi.org\/10.1016\/j.jsbmb.2015.04.016","journal-title":"J Steroid Biochem Mol Biol"},{"key":"942_CR46","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1161\/01.cir.0000013839.41224.1c","volume":"105","author":"DB Sawyer","year":"2002","unstructured":"Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM (2002) Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation 105:1551\u20131554. https:\/\/doi.org\/10.1161\/01.cir.0000013839.41224.1c","journal-title":"Circulation"},{"key":"942_CR47","doi-asserted-by":"publisher","first-page":"2476","DOI":"10.1016\/j.jacc.2017.08.074","volume":"70","author":"KS Shah","year":"2017","unstructured":"Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, Devore AD, Yancy CW, Fonarow GC (2017) Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol 70:2476\u20132486. https:\/\/doi.org\/10.1016\/j.jacc.2017.08.074","journal-title":"J Am Coll Cardiol"},{"key":"942_CR48","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m2688","volume":"370","author":"NS Shah","year":"2020","unstructured":"Shah NS, Molsberry R, Rana JS, Sidney S, Capewell S, O\u2019Flaherty M, Carnethon M, Lloyd-Jones DM, Khan SS (2020) Heterogeneous trends in burden of heart disease mortality by subtypes in the United States, 1999\u20132018: observational analysis of vital statistics. BMJ 370:m2688. https:\/\/doi.org\/10.1136\/bmj.m2688","journal-title":"BMJ"},{"key":"942_CR49","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1161\/CIRCRESAHA.118.311208","volume":"123","author":"RJ Vagnozzi","year":"2018","unstructured":"Vagnozzi RJ, Molkentin JD, Houser SR (2018) New myocyte formation in the adult heart: endogenous sources and therapeutic implications. Circ Res 123:159\u2013176. https:\/\/doi.org\/10.1161\/CIRCRESAHA.118.311208","journal-title":"Circ Res"},{"key":"942_CR50","doi-asserted-by":"publisher","first-page":"2233","DOI":"10.1111\/j.1582-4934.2008.00439.x","volume":"12","author":"MJ van Amerongen","year":"2008","unstructured":"van Amerongen MJ, Engel FB (2008) Features of cardiomyocyte proliferation and its potential for cardiac regeneration. J Cell Mol Med 12:2233\u20132244. https:\/\/doi.org\/10.1111\/j.1582-4934.2008.00439.x","journal-title":"J Cell Mol Med"},{"key":"942_CR51","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1046\/j.1365-2184.2003.00267.x","volume":"36","author":"K Vermeulen","year":"2003","unstructured":"Vermeulen K, Berneman ZN, Van Bockstaele DR (2003) Cell cycle and apoptosis. Cell Prolif 36:165\u2013175. https:\/\/doi.org\/10.1046\/j.1365-2184.2003.00267.x","journal-title":"Cell Prolif"},{"key":"942_CR52","doi-asserted-by":"publisher","first-page":"e254","DOI":"10.1161\/CIR.0000000000000950","volume":"143","author":"SS Virani","year":"2021","unstructured":"Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, Elkind MSV, Evenson KR, Ferguson JF, Gupta DK, Khan SS, Kissela BM, Knutson KL, Lee CD, Lewis TT, Liu J, Loop MS, Lutsey PL, Ma J, Mackey J, Martin SS, Matchar DB, Mussolino ME, Navaneethan SD, Perak AM, Roth GA, Samad Z, Satou GM, Schroeder EB, Shah SH, Shay CM, Stokes A, VanWagner LB, Wang NY, Tsao CW, American Heart Association Council on E, Prevention Statistics C, Stroke Statistics S (2021) Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation 143:e254\u2013e743. https:\/\/doi.org\/10.1161\/CIR.0000000000000950","journal-title":"Circulation"},{"key":"942_CR53","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1093\/oxfordjournals.eurheartj.a059928","volume":"12","author":"HW Vliegen","year":"1991","unstructured":"Vliegen HW, van der Laarse A, Cornelisse CJ, Eulderink F (1991) Myocardial changes in pressure overload-induced left ventricular hypertrophy. A study on tissue composition, polyploidization and multinucleation. Eur Heart J 12:488\u2013494. https:\/\/doi.org\/10.1093\/oxfordjournals.eurheartj.a059928","journal-title":"Eur Heart J"},{"key":"942_CR54","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1172\/JCI17664","volume":"111","author":"D Wencker","year":"2003","unstructured":"Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, Kitsis RN (2003) A mechanistic role for cardiac myocyte apoptosis in heart failure. J Clin Invest 111:1497\u20131504. https:\/\/doi.org\/10.1172\/JCI17664","journal-title":"J Clin Invest"},{"key":"942_CR55","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1161\/hh2401.100742","volume":"89","author":"G Xiao","year":"2001","unstructured":"Xiao G, Mao S, Baumgarten G, Serrano J, Jordan MC, Roos KP, Fishbein MC, MacLellan WR (2001) Inducible activation of c-Myc in adult myocardium in vivo provokes cardiac myocyte hypertrophy and reactivation of DNA synthesis. Circ Res 89:1122\u20131129. https:\/\/doi.org\/10.1161\/hh2401.100742","journal-title":"Circ Res"},{"key":"942_CR56","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1172\/JCI17459","volume":"111","author":"S Yamamoto","year":"2003","unstructured":"Yamamoto S, Yang G, Zablocki D, Liu J, Hong C, Kim SJ, Soler S, Odashima M, Thaisz J, Yehia G, Molina CA, Yatani A, Vatner DE, Vatner SF, Sadoshima J (2003) Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy. J Clin Invest 111:1463\u20131474. https:\/\/doi.org\/10.1172\/JCI17459","journal-title":"J Clin Invest"},{"key":"942_CR57","doi-asserted-by":"publisher","first-page":"3312","DOI":"10.1128\/MCB.00229-15","volume":"35","author":"G Yan","year":"2015","unstructured":"Yan G, Zhu N, Huang S, Yi B, Shang X, Chen M, Wang N, Zhang GX, Talarico JA, Tilley DG, Gao E, Sun J (2015) Orphan nuclear receptor Nur77 inhibits cardiac hypertrophic response to beta-adrenergic stimulation. Mol Cell Biol 35:3312\u20133323. https:\/\/doi.org\/10.1128\/MCB.00229-15","journal-title":"Mol Cell Biol"},{"key":"942_CR58","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1161\/01.cir.98.7.656","volume":"98","author":"A Zafeiridis","year":"1998","unstructured":"Zafeiridis A, Jeevanandam V, Houser SR, Margulies KB (1998) Regression of cellular hypertrophy after left ventricular assist device support. Circulation 98:656\u2013662. https:\/\/doi.org\/10.1161\/01.cir.98.7.656","journal-title":"Circulation"},{"key":"942_CR59","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1016\/0046-8177(92)90064-a","volume":"23","author":"C Zerbini","year":"1992","unstructured":"Zerbini C, Weinberg DS, Perez-Atayde AR (1992) DNA ploidy analysis of myocardial hyperplasia. Hum Pathol 23:1427\u20131430. https:\/\/doi.org\/10.1016\/0046-8177(92)90064-a","journal-title":"Hum Pathol"},{"key":"942_CR60","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.012731","volume":"8","author":"Q Zhao","year":"2019","unstructured":"Zhao Q, Sun Q, Zhou L, Liu K, Jiao K (2019) Complex regulation of mitochondrial function during cardiac development. J Am Heart Assoc 8:e012731. https:\/\/doi.org\/10.1161\/JAHA.119.012731","journal-title":"J Am Heart Assoc"},{"key":"942_CR61","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1007\/s00395-018-0682-1","volume":"113","author":"H Zhou","year":"2018","unstructured":"Zhou H, Wang J, Zhu P, Zhu H, Toan S, Hu S, Ren J, Chen Y (2018) NR4A1 aggravates the cardiac microvascular ischemia reperfusion injury through suppressing FUNDC1-mediated mitophagy and promoting Mff-required mitochondrial fission by CK2alpha. Basic Res Cardiol 113:23. https:\/\/doi.org\/10.1007\/s00395-018-0682-1","journal-title":"Basic Res Cardiol"},{"key":"942_CR62","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1161\/CIRCRESAHA.116.308544","volume":"118","author":"J Zhou","year":"2016","unstructured":"Zhou J, Ahmad F, Parikh S, Hoffman NE, Rajan S, Verma VK, Song J, Yuan A, Shanmughapriya S, Guo Y, Gao E, Koch W, Woodgett JR, Madesh M, Kishore R, Lal H, Force T (2016) Loss of adult cardiac myocyte GSK-3 leads to mitotic catastrophe resulting in fatal dilated cardiomyopathy. Circ Res 118:1208\u20131222. https:\/\/doi.org\/10.1161\/CIRCRESAHA.116.308544","journal-title":"Circ Res"},{"key":"942_CR63","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1161\/CIRCRESAHA.117.311504","volume":"122","author":"W Zhu","year":"2018","unstructured":"Zhu W, Zhao M, Mattapally S, Chen S, Zhang J (2018) CCND2 overexpression enhances the regenerative potency of human induced pluripotent stem cell-derived cardiomyocytes: remuscularization of injured ventricle. Circ Res 122:88\u201396. https:\/\/doi.org\/10.1161\/CIRCRESAHA.117.311504","journal-title":"Circ Res"},{"key":"942_CR64","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.yjmcc.2020.11.016","volume":"152","author":"Y Zhu","year":"2021","unstructured":"Zhu Y, Do VD, Richards AM, Foo R (2021) What we know about cardiomyocyte dedifferentiation. J Mol Cell Cardiol 152:80\u201391. https:\/\/doi.org\/10.1016\/j.yjmcc.2020.11.016","journal-title":"J Mol Cell Cardiol"}],"container-title":["Basic Research in Cardiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00395-022-00942-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00395-022-00942-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00395-022-00942-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T12:08:47Z","timestamp":1675080527000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00395-022-00942-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,1]]},"references-count":64,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["942"],"URL":"https:\/\/doi.org\/10.1007\/s00395-022-00942-7","relation":{},"ISSN":["0300-8428","1435-1803"],"issn-type":[{"value":"0300-8428","type":"print"},{"value":"1435-1803","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,1]]},"assertion":[{"value":"1 November 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 June 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 June 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2022","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"33"}}