{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T15:25:36Z","timestamp":1788449136042,"version":"build-2803163510"},"reference-count":69,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82030010"],"award-info":[{"award-number":["82030010"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870231"],"award-info":[{"award-number":["81870231"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81370233"],"award-info":[{"award-number":["81370233"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Regulated necrosis (necroptosis) and apoptosis are important biological features of myocardial infarction, ischaemia-reperfusion (I\/R) injury, and heart failure. However, the molecular mechanisms underlying myocardial necroptosis remain elusive. Ischaemic preconditioning (IPC) is the most powerful intrinsic cardioprotection against myocardial I\/R injury. In this study, we aimed to determine whether IPC suppresses I\/R-induced necroptosis and the underlying molecular mechanisms.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>We generated p55\u03b3 transgenic and knockout mice and used ligation of left anterior descending coronary artery to produce an in vivo I\/R model. The effects of p55\u03b3 and its downstream molecules were subsequently identified using mass spectroscopy and co-immunoprecipitation and pulldown assays. We found that p55\u03b3 expression was down-regulated in failing human myocardium caused by coronary heart disease as well as in I\/R mouse hearts. Cardiac-specific p55\u03b3 overexpression ameliorated the I\/R-induced necroptosis. In striking contrast, p55\u03b3 deficiency (p55\u03b3\u2212\/\u2212) and cardiac-specific deletion of p55\u03b3 (p55\u03b3c-KO) worsened I\/R-induced injury. IPC up-regulated p55\u03b3 expression in vitro and in vivo. Using reporter and chromatin immunoprecipitation assays, we found that Hif1\u03b1 transcriptionally regulated p55\u03b3 expression and mediated the cardioprotection of IPC. IPC-mediated suppression of necroptosis was attenuated in p55\u03b3\u2212\/\u2212 and p55\u03b3c-KO hearts. Mechanistically, p55\u03b3 overexpression decreased the protein levels of RIP3 rather than the mRNA levels, while p55\u03b3 deficiency increased the protein abundance of RIP3. IPC attenuated the I\/R-induced up-regulation of RIP3, which was abolished in p55\u03b3-deficient mice. Up-regulation of RIP3 attenuated the p55\u03b3- or IPC-induced inhibition of necroptosis in vivo. Importantly, p55\u03b3 directly bound and degraded RIP3 in a ubiquitin-dependent manner. We identified MG53 as the E3 ligase that mediated the p55\u03b3-induced degradation of RIP3. In addition, we also found that p55\u03b3 activated the RISK pathway during IPC.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Our findings reveal that activation of the MG53-RIP3 signal pathway by p55\u03b3 protects the heart against I\/R-induced necroptosis and underlies IPC-induced cardioprotection.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvad123","type":"journal-article","created":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T20:59:19Z","timestamp":1690923559000},"page":"2421-2440","source":"Crossref","is-referenced-by-count":22,"title":["p55\u03b3 degrades RIP3 via MG53 to suppress ischaemia-induced myocardial necroptosis and mediates cardioprotection of preconditioning"],"prefix":"10.1093","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0319-2832","authenticated-orcid":false,"given":"Zhenyan","family":"Li","sequence":"first","affiliation":[{"name":"Laboratory of Cardiovascular Science, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University , 95 Yongan Road, Xicheng District, Beijing 100050 , China"},{"name":"Department of Physiology, Capital Institute of Pediatrics , 2 Yabao Road, Chaoyang District, Beijing 100020 , China"},{"name":"Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences , 9 Dongdansantiao, Dongcheng District, Beijing 100730 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1218-2174","authenticated-orcid":false,"given":"Rilei","family":"Dai","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University , 95 Yongan Road, Xicheng District, Beijing 100050 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8722-6883","authenticated-orcid":false,"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology, Capital Institute of Pediatrics , 2 Yabao Road, Chaoyang District, Beijing 100020 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5853-4265","authenticated-orcid":false,"given":"Lixuan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The Fourth Hospital of Hebei Medical University, Hebei Medical University , 361 Zhongshan East Road, Shijiazhuang 050017 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4499-1905","authenticated-orcid":false,"given":"Kun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University , 95 Yongan Road, Xicheng District, Beijing 100050 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0354-1542","authenticated-orcid":false,"given":"Mingyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Beijing Friendship Hospital, Capital Medical University , 95 Yongan Road, Xicheng District, Beijing 100050 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8680-7910","authenticated-orcid":false,"given":"Wenting","family":"Zhu","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University , 95 Yongan Road, Xicheng District, Beijing 100050 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5777-8329","authenticated-orcid":false,"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Laboratory of Cardiovascular Science, Beijing Clinical Research Institute, Beijing Friendship Hospital, Capital Medical University , 95 Yongan Road, Xicheng District, Beijing 100050 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6559-2997","authenticated-orcid":false,"given":"Ning","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine, Peking University , 5 Yiheyuan Road, Haidian District, Beijing 100871 , 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