{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T00:03:53Z","timestamp":1773446633081,"version":"3.50.1"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"19","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2022,10,4]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">The postmitotic state of adult cardiomyocytes, maintained by the cell cycle repressor Rbl2 (retinoblastoma\u2010like 2), is associated with considerable resistance to apoptosis. However, whether Rbl2 regulates cardiomyocyte apoptosis remains unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Here, we show that ablation of Rbl2 increased cardiomyocyte apoptosis following acute myocardial ischemia\/reperfusion injury, leading to diminished cardiac function and exaggerated ventricular remodeling in the long term. Mechanistically, ischemia\/reperfusion induced expression of the proapoptotic protein BCL2 interacting protein 3 (Bnip3), which was augmented by deletion of Rbl2. Because the Bnip3 promoter contains an adenoviral early region 2 binding factor (E2F)\u2010binding site, we further showed that loss of Rbl2 upregulated the transcriptional activator E2F1 but downregulated the transcriptional repressor E2F4. In cultured cardiomyocytes, treatment with H\n              <jats:sub>2<\/jats:sub>\n              O\n              <jats:sub>2<\/jats:sub>\n              markedly increased the levels of E2F1 and Bnip3, resulting in mitochondrial depolarization and apoptosis. Depletion of Rbl2 significantly augmented H\n              <jats:sub>2<\/jats:sub>\n              O\n              <jats:sub>2<\/jats:sub>\n              \u2010induced mitochondrial damage and apoptosis in vitro.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Rbl2 deficiency enhanced E2F1\u2010mediated Bnip3 expression, resulting in aggravated cardiomyocyte apoptosis and ischemia\/reperfusion injury. Our results uncover a novel antiapoptotic role for Rbl2 in cardiomyocytes, suggesting that the cell cycle machinery may directly regulate apoptosis in postmitotic cardiomyocytes. These findings may be exploited to develop new strategies to limit ischemia\/reperfusion injury in the treatment of acute myocardial infarction.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.121.024764","type":"journal-article","created":{"date-parts":[[2022,9,21]],"date-time":"2022-09-21T10:42:14Z","timestamp":1663756934000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["Loss of Rbl2 (Retinoblastoma\u2010Like 2) Exacerbates Myocardial Ischemia\/Reperfusion Injury"],"prefix":"10.1161","volume":"11","author":[{"given":"Jingrui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences Washington State University Spokane Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Washington State University Spokane Washington"},{"name":"Cardiovascular Research Center, Department of Medicine Massachusetts General Hospital, Harvard Medical School Boston Massachusetts"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6891-0006","authenticated-orcid":false,"given":"Yuening","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Washington State University Spokane Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8989-0350","authenticated-orcid":false,"given":"Clark","family":"Kogan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Washington State University Spokane Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9646-4824","authenticated-orcid":false,"given":"Zhaokang","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Washington State University Spokane Washington"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000950"},{"key":"e_1_3_1_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-020-0403-y"},{"key":"e_1_3_1_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00844.2011"},{"key":"e_1_3_1_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.11.011"},{"key":"e_1_3_1_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00032.2006"},{"key":"e_1_3_1_7_2","first-page":"641","article-title":"Cell cycle proteins as key regulators of postmitotic cell death","volume":"92","author":"Xia P","year":"2019","unstructured":"Xia P, Liu Y, Chen J, Cheng Z. Cell cycle proteins as key regulators of postmitotic cell death. Yale J Biol Med. 2019;92:641\u2013650.","journal-title":"Yale J Biol Med"},{"key":"e_1_3_1_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24170"},{"key":"e_1_3_1_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.6.2486-2497.2005"},{"key":"e_1_3_1_10_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201012049"},{"key":"e_1_3_1_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.118.314063"},{"key":"e_1_3_1_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.012089"},{"key":"e_1_3_1_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2008.07.003"},{"key":"e_1_3_1_14_2","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.50992"},{"key":"e_1_3_1_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14664"},{"key":"e_1_3_1_16_2","first-page":"3850","article-title":"Loss of pRb2\/p130 expression is associated with unfavorable clinical outcome in lung cancer","volume":"8","author":"Caputi M","year":"2002","unstructured":"Caputi M, Groeger AM, Esposito V, De Luca A, Masciullo V, Mancini A, Baldi F, Wolner E, Giordano A. Loss of pRb2\/p130 expression is associated with unfavorable clinical outcome in lung cancer. Clin Cancer Res. 2002;8:3850\u20133856.","journal-title":"Clin Cancer Res"},{"key":"e_1_3_1_17_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.10.13.1633"},{"key":"e_1_3_1_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA118.004673"},{"key":"e_1_3_1_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100850"},{"key":"e_1_3_1_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/20.3.422"},{"key":"e_1_3_1_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401231"},{"key":"e_1_3_1_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000029232.42227.16"},{"key":"e_1_3_1_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32490"},{"key":"e_1_3_1_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401936"},{"key":"e_1_3_1_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.164731"},{"key":"e_1_3_1_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2004.06.006"},{"key":"e_1_3_1_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-019-0143-7"},{"key":"e_1_3_1_28_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1296405"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0214-3"},{"key":"e_1_3_1_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401499"},{"key":"e_1_3_1_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205750"},{"key":"e_1_3_1_32_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0996"},{"key":"e_1_3_1_33_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA119.011571"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.09.004"},{"key":"e_1_3_1_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000159705.17322.57"},{"key":"e_1_3_1_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.85.2.128"},{"key":"e_1_3_1_37_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119817"},{"key":"e_1_3_1_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2011.09.012"},{"key":"e_1_3_1_39_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.574145"},{"key":"e_1_3_1_40_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00552.2008"},{"key":"e_1_3_1_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1414665111"},{"key":"e_1_3_1_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.12"},{"key":"e_1_3_1_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb998"},{"key":"e_1_3_1_44_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv885"}],"container-title":["Journal of the American Heart Association"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/JAHA.121.024764","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T10:56:40Z","timestamp":1715597800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/JAHA.121.024764"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,4]]},"references-count":43,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2022,10,4]]}},"alternative-id":["10.1161\/JAHA.121.024764"],"URL":"https:\/\/doi.org\/10.1161\/jaha.121.024764","relation":{},"ISSN":["2047-9980"],"issn-type":[{"value":"2047-9980","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,4]]},"assertion":[{"value":"2021-11-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-02","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-09-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e024764"}}