{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:19:15Z","timestamp":1790734755370,"version":"4.1.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81770402"],"award-info":[{"award-number":["81770402"]}],"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":["81520108004"],"award-info":[{"award-number":["81520108004"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013290","name":"MOST | National Key Research and Development Program of China Stem Cell and Translational Research","doi-asserted-by":"publisher","award":["2017YFA0103700"],"award-info":[{"award-number":["2017YFA0103700"]}],"id":[{"id":"10.13039\/501100013290","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013290","name":"MOST | National Key Research and Development Program of China Stem Cell and Translational Research","doi-asserted-by":"publisher","award":["2016YFC1301200"],"award-info":[{"award-number":["2016YFC1301200"]}],"id":[{"id":"10.13039\/501100013290","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Strategic Priority Research Program of the CAS [CHINA]","award":["No. XDA16010201"],"award-info":[{"award-number":["No. XDA16010201"]}]},{"DOI":"10.13039\/501100013290","name":"MOST | National Key Research and Development Program of China Stem Cell and Translational Research","doi-asserted-by":"publisher","award":["(SQ2018YFA050005"],"award-info":[{"award-number":["(SQ2018YFA050005"]}],"id":[{"id":"10.13039\/501100013290","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013290","name":"MOST | National Key Research and Development Program of China Stem Cell and Translational Research","doi-asserted-by":"publisher","award":["2018YFA0109100"],"award-info":[{"award-number":["2018YFA0109100"]}],"id":[{"id":"10.13039\/501100013290","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012541","name":"Guangdong Innovative and Entrepreneurial Research Team Program","doi-asserted-by":"publisher","award":["2016ZT06S029"],"award-info":[{"award-number":["2016ZT06S029"]}],"id":[{"id":"10.13039\/100012541","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Jiao Tong University Affiliated Sixth People's Hospital"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,9,11]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>Impaired autophagic flux contributes to ischemia\/reperfusion (I\/R)-induced cardiomyocyte death, but the underlying molecular mechanisms remain largely unexplored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>To determine the role of LAPTM4B (lysosomal-associated transmembrane protein 4B) in the regulation of autophagic flux and myocardial I\/R injury.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              LAPTM4B was expressed in murine hearts but downregulated in hearts with I\/R (30 minutes\/2 hours) injury and neonatal rat cardiomyocytes with hypoxia\/reoxygenation (6 hours\/2 hours) injury. During myocardial reperfusion, LAPTM4B-knockout (LAPTM4B\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              ) mice had a significantly increased infarct size and lactate dehydrogenase release, whereas adenovirus-mediated LAPTM4B-overexpression was cardioprotective. Concomitantly, LAPTM4B\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice showed higher accumulation of the autophagy markers LC3-II (microtubule-associated protein 1A\/1B-light chain 3), but not P62, in the I\/R heart, whereas they did not alter chloroquine-induced further increases of LC3-II and P62 in both sham and I\/R hearts. Conversely, LAPTM4B-overexpression had opposite effects. The hypoxia\/reoxygenation\u2013reduced viability of neonatal rat cardiomyocytes, ratio of autolysosomes\/autophagosomes, and function of lysosomes were further decreased by LAPTM4B-knockdown but reversed by LAPTM4B-overexpression. Moreover, the LAPTM4B-overexpression\u2013mediated benefits were abolished by knockdown of lysosome-associated membrane protein-2 (an autophagosome-lysosome fusion protein) in vivo and by the autophagy inhibitor bafilomycin A1 in vivo. In contrast, rapamycin (Rapa) successfully restored the impaired autophagic flux in LAPTM4B\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice and the subsequent myocardial I\/R injury. Mechanistically, LAPTM4B regulated the activity of mTORC1 (mammalian target of rapamycin complex 1) via interacting with mTOR through its EC3 (extracelluar) domain. Thus, mTORC1 was overactivated in LAPTM4B\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice, leading to the repression of TFEB (transcription factor EB), a master regulator of lysosomal and autophagic genes, during myocardial I\/R. The mTORC1 inhibition or TFEB-overexpression rescued the LAPTM4B\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              -induced impairment in autophagic flux and I\/R injury, whereas TFEB-knockdown abolished the LAPTM4B-overexpression\u2013mediated recovery of autophagic flux and cardioprotection.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>The downregulation of LAPTM4B contributes to myocardial I\/R\u2013induced impairment of autophagic flux via modulation of the mTORC1\/TFEB pathway.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Graphic Abstract:<\/jats:title>\n            <jats:p>\n              A\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.119.316388\">graphic abstract<\/jats:ext-link>\n              is available for this article.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.119.316388","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T09:00:50Z","timestamp":1595408450000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":125,"title":["Downregulation of LAPTM4B Contributes to the Impairment of the Autophagic Flux via Unopposed Activation of mTORC1 Signaling During Myocardial Ischemia\/Reperfusion Injury"],"prefix":"10.1161","volume":"127","author":[{"given":"Shanshan","family":"Gu","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."},{"name":"Program of Stem Cells and Regenerative Medicine, Zhongshan School of Medicine and The Fifth Affiliated Hospital, Sun Yat-Sen University, Guangdong, P.R. China (S.G., N.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiliang","family":"Tan","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Li","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenyan","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People\u2019s Hospital, P.R. China (J.M., M.W., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Zheng","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinlong","family":"Liu","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Bi","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Sha","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuxia","family":"Li","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People\u2019s Hospital, P.R. China (J.M., M.W., H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1660-4728","authenticated-orcid":true,"given":"Nan","family":"Cao","sequence":"additional","affiliation":[{"name":"Program of Stem Cells and Regenerative Medicine, Zhongshan School of Medicine and The Fifth Affiliated Hospital, Sun Yat-Sen University, Guangdong, P.R. China (S.G., N.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6297-9037","authenticated-orcid":true,"given":"Huang-Tian","family":"Yang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS (S.G., J.T., Q.L., S.L., Y.Z., J.L., W.B., P.S., X.L., H.-T.Y.)."},{"name":"Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People\u2019s Hospital, P.R. China (J.M., M.W., H.-T.Y.)."},{"name":"Institute for Stem Cell and Regeneration, CAS, Beijing, P.R. China (H.-T.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra071667"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000261924.76669.36"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.041814"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021317-121427"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2009.11.014"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-122313-085916"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160385"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.017443"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e02-02-0114"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/35022595"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1206832"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.12.006"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-0940"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160780"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311147"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2017.10.003"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.09.007"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.4161\/auto.21544"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e04-02-0103"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12613"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607128200"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1157535"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/35022604"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2017.1358848"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.249532"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(02)00808-5"},{"key":"e_1_3_6_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms8250"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1063768"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.04.025"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvu256"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12351-x"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2018.7688"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-59745-571-8_16"}],"updated-by":[{"DOI":"10.1161\/res.0000000000000597","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000}}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.119.316388","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T05:17:39Z","timestamp":1715577459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.119.316388"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,11]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2020,9,11]]}},"alternative-id":["10.1161\/CIRCRESAHA.119.316388"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.119.316388","relation":{"correction":[{"id-type":"doi","id":"10.1161\/RES.0000000000000597","asserted-by":"object"}]},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,11]]},"assertion":[{"value":"2020-11-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-07-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}