{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:41:08Z","timestamp":1792201268663,"version":"4.4.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Abdominal aortic aneurysm (AAA), an irreversible cardiovascular disease prevalent in the artery, causes the increase of the aneurysm diameter over time, and is a fatal phenomenon inducing sidewall rupture. Long noncoding RNAs (lncRNAs) serve as promising biomarkers for AAA. In the present study, we sought to define the role of lncRNA growth-arrest-specific transcript 5 (GAS5) in growth of smooth muscle cells (SMC) and progression of AAA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Initially, we established angiotensin II (Ang II)-induced AAA mouse models and Ang II-treated vascular SMC model. RT-qPCR and Western blot analysis were adopted to determine expression of GAS5 and zeste homolog 2 (EZH2). After ectopic expression and depletion experiments in Ang II-treated mice and vascular SMCs, cell apoptosis was detected in SMCs using flow cytometry and in mice using TUNEL staining. The binding of GAS5 and EZH2 was evaluated using RNA binding protein immunoprecipitation (RIP) and Co-IP assays.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Increased GAS5 and RIG-I but decreased EZH2 were found in aortic tissues of AAA mice. EZH2 overexpression inhibited AAA formation and suppressed SMC apoptosis. Functionally, EZH2 blocked the RIG-I signaling pathway and consequently inhibited SMC apoptosis. GAS5 regulated EZH2 transcription in a negative manner in SMCs. Knockdown of GAS5 attenuated SMC apoptosis, which was reversed by EZH2 inhibition or RIG-I overexpression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The current study demonstrated that GAS5 induced SMC apoptosis and subsequent AAA onset by activating EZH2-mediated RIG-I signaling pathway, highlighting GAS5 as a novel biomarker for AAA.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12967-021-03023-w","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T13:02:59Z","timestamp":1636981379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Knockdown of long noncoding RNA GAS5 reduces vascular smooth muscle cell apoptosis by inactivating EZH2-mediated RIG-I signaling pathway in abdominal aortic aneurysm"],"prefix":"10.1186","volume":"19","author":[{"given":"Tianming","family":"Le","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kemin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"3023_CR1","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1016\/j.cell.2018.07.021","volume":"174","author":"J Li","year":"2018","unstructured":"Li J, Pan C, Zhang S, Spin JM, Deng A, Leung LLK, et al. Decoding the genomics of abdominal aortic aneurysm. Cell. 2018;174:1361-72.e10.","journal-title":"Cell"},{"key":"3023_CR2","doi-asserted-by":"publisher","first-page":"2473","DOI":"10.1084\/jem.20151794","volume":"213","author":"Y Liu","year":"2016","unstructured":"Liu Y, Wang TT, Zhang R, Fu WY, Wang X, Wang F, et al. Calorie restriction protects against experimental abdominal aortic aneurysms in mice. J Exp Med. 2016;213:2473\u201388.","journal-title":"J Exp Med"},{"key":"3023_CR3","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/s41419-017-0213-2","volume":"9","author":"R Li","year":"2018","unstructured":"Li R, Yi X, Wei X, Huo B, Guo X, Cheng C, et al. EZH2 inhibits autophagic cell death of aortic vascular smooth muscle cells to affect aortic dissection. Cell Death Dis. 2018;9:180.","journal-title":"Cell Death Dis"},{"key":"3023_CR4","doi-asserted-by":"publisher","first-page":"1032","DOI":"10.1007\/s00261-017-1450-7","volume":"43","author":"BW Ullery","year":"2018","unstructured":"Ullery BW, Hallett RL, Fleischmann D. Epidemiology and contemporary management of abdominal aortic aneurysms. Abdom Radiol. 2018;43:1032\u201343.","journal-title":"Abdom Radiol"},{"key":"3023_CR5","first-page":"11","volume":"16","author":"S Aggarwal","year":"2011","unstructured":"Aggarwal S, Qamar A, Sharma V, Sharma A. Abdominal aortic aneurysm: a comprehensive review. Exp Clin Cardiol. 2011;16:11\u20135.","journal-title":"Exp Clin Cardiol"},{"key":"3023_CR6","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1093\/cvr\/cvp155","volume":"83","author":"T Miyake","year":"2009","unstructured":"Miyake T, Morishita R. Pharmacological treatment of abdominal aortic aneurysm. Cardiovasc Res. 2009;83:436\u201343.","journal-title":"Cardiovasc Res"},{"key":"3023_CR7","doi-asserted-by":"publisher","first-page":"H652","DOI":"10.1152\/ajpheart.00621.2019","volume":"318","author":"B Liu","year":"2020","unstructured":"Liu B, Granville DJ, Golledge J, Kassiri Z. Pathogenic mechanisms and the potential of drug therapies for aortic aneurysm. Am J Physiol Heart Circ Physiol. 2020;318:H652-70.","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"3023_CR8","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1161\/CIRCRESAHA.118.312438","volume":"124","author":"S Kumar","year":"2019","unstructured":"Kumar S, Boon RA, Maegdefessel L, Dimmeler S, Jo H. Role of noncoding RNAs in the pathogenesis of abdominal aortic aneurysm. Circ Res. 2019;124:619\u201330.","journal-title":"Circ Res"},{"key":"3023_CR9","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1089\/ars.2020.8035","volume":"33","author":"C Knappich","year":"2020","unstructured":"Knappich C, Spin JM, Eckstein HH, Tsao PS, Maegdefessel L. Involvement of myeloid cells and noncoding RNA in abdominal aortic aneurysm disease. Antioxid Redox Signal. 2020;33:602\u201320.","journal-title":"Antioxid Redox Signal"},{"key":"3023_CR10","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.atherosclerosis.2019.11.013","volume":"292","author":"ZY Wu","year":"2020","unstructured":"Wu ZY, Trenner M, Boon RA, Spin JM, Maegdefessel L. Long noncoding RNAs in key cellular processes involved in aortic aneurysms. Atherosclerosis. 2020;292:112\u20138.","journal-title":"Atherosclerosis"},{"key":"3023_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2020.109575","volume":"70","author":"Z Li","year":"2020","unstructured":"Li Z, Kong W. Cellular signaling in abdominal aortic aneurysm. Cell Signal. 2020;70: 109575.","journal-title":"Cell Signal"},{"key":"3023_CR12","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.bbrc.2018.01.022","volume":"496","author":"F Chen","year":"2018","unstructured":"Chen F, Zhang L, Wang E, Zhang C, Li X. LncRNA GAS5 regulates ischemic stroke as a competing endogenous RNA for miR-137 to regulate the Notch1 signaling pathway. Biochem Biophys Res Commun. 2018;496:184\u201390.","journal-title":"Biochem Biophys Res Commun"},{"key":"3023_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2019.109302","volume":"118","author":"S Shen","year":"2019","unstructured":"Shen S, Zheng X, Zhu Z, Zhao S, Zhou Q, Song Z, et al. Silencing of GAS5 represses the malignant progression of atherosclerosis through upregulation of miR-135a. Biomed Pharmacother. 2019;118: 109302.","journal-title":"Biomed Pharmacother"},{"key":"3023_CR14","doi-asserted-by":"publisher","first-page":"5558","DOI":"10.7150\/thno.34463","volume":"9","author":"X He","year":"2019","unstructured":"He X, Wang S, Li M, Zhong L, Zheng H, Sun Y, et al. Long noncoding RNA GAS5 induces abdominal aortic aneurysm formation by promoting smooth muscle apoptosis. Theranostics. 2019;9:5558\u201376.","journal-title":"Theranostics"},{"key":"3023_CR15","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.omtn.2019.10.034","volume":"19","author":"XD Meng","year":"2020","unstructured":"Meng XD, Yao HH, Wang LM, Yu M, Shi S, Yuan ZX, et al. Knockdown of GAS5 inhibits atherosclerosis progression via reducing EZH2-mediated ABCA1 transcription in ApoE(\u2212\/\u2212) mice. Mol Ther Nucleic Acids. 2020;19:84\u201396.","journal-title":"Mol Ther Nucleic Acids"},{"key":"3023_CR16","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1161\/CIRCULATIONAHA.117.028561","volume":"136","author":"R Papait","year":"2017","unstructured":"Papait R, Serio S, Pagiatakis C, Rusconi F, Carullo P, Mazzola M, et al. Histone methyltransferase G9a is required for cardiomyocyte homeostasis and hypertrophy. Circulation. 2017;136:1233\u201346.","journal-title":"Circulation"},{"key":"3023_CR17","doi-asserted-by":"publisher","first-page":"51","DOI":"10.3389\/fimmu.2020.00051","volume":"11","author":"A Li","year":"2020","unstructured":"Li A, Wang W, Wang Y, Chen K, Xiao F, Hu D, et al. NS5 conservative site is required for Zika virus to restrict the RIG-I signaling. Front Immunol. 2020;11:51.","journal-title":"Front Immunol"},{"key":"3023_CR18","doi-asserted-by":"publisher","first-page":"2614","DOI":"10.4049\/jimmunol.1203143","volume":"191","author":"S Chen","year":"2013","unstructured":"Chen S, Sheng C, Liu D, Yao C, Gao S, Song L, et al. Enhancer of zeste homolog 2 is a negative regulator of mitochondria-mediated innate immune responses. J Immunol. 2013;191:2614\u201323.","journal-title":"J Immunol"},{"key":"3023_CR19","doi-asserted-by":"publisher","first-page":"7942","DOI":"10.1074\/jbc.RA118.002046","volume":"293","author":"B Ramachandran","year":"2018","unstructured":"Ramachandran B, Stabley JN, Cheng SL, Behrmann AS, Gay A, Li L, et al. A GTPase-activating protein-binding protein (G3BP1)\/antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells. J Biol Chem. 2018;293:7942\u201368.","journal-title":"J Biol Chem"},{"key":"3023_CR20","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1161\/ATVBAHA.119.314113","volume":"40","author":"Z Li","year":"2020","unstructured":"Li Z, Zhao Z, Cai Z, Sun Y, Li L, Yao F, et al. Runx2 (runt-related transcription factor 2)-mediated microcalcification is a novel pathological characteristic and potential mediator of abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 2020;40:1352\u201369.","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"3023_CR21","doi-asserted-by":"publisher","first-page":"39S","DOI":"10.1016\/j.jvs.2017.10.087","volume":"68","author":"A Jablonska","year":"2018","unstructured":"Jablonska A, Neumayer C, Bolliger M, Gollackner B, Klinger M, Paradowska E, et al. Analysis of host Toll-like receptor 3 and RIG-I-like receptor gene expression in patients with abdominal aortic aneurysm. J Vasc Surg. 2018;68:39S-46S.","journal-title":"J Vasc Surg"},{"key":"3023_CR22","doi-asserted-by":"publisher","DOI":"10.3791\/53191","author":"H Lu","year":"2015","unstructured":"Lu H, Howatt DA, Balakrishnan A, Moorleghen JJ, Rateri DL, Cassis LA, et al. Subcutaneous angiotensin II infusion using osmotic pumps induces aortic aneurysms in mice. J Vis Exp. 2015. https:\/\/doi.org\/10.3791\/53191.","journal-title":"J Vis Exp"},{"key":"3023_CR23","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1161\/CIRCRESAHA.117.311450","volume":"121","author":"G Zhao","year":"2017","unstructured":"Zhao G, Fu Y, Cai Z, Yu F, Gong Z, Dai R, et al. Unspliced XBP1 confers VSMC homeostasis and prevents aortic aneurysm formation via FoxO4 interaction. Circ Res. 2017;121:1331\u201345.","journal-title":"Circ Res"},{"key":"3023_CR24","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1093\/cvr\/cvr080","volume":"91","author":"H Kaneko","year":"2011","unstructured":"Kaneko H, Anzai T, Takahashi T, Kohno T, Shimoda M, Sasaki A, et al. Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm. Cardiovasc Res. 2011;91:358\u201367.","journal-title":"Cardiovasc Res"},{"key":"3023_CR25","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/0006-291X(76)90501-5","volume":"73","author":"JE Mole","year":"1976","unstructured":"Mole JE, Bhown AD, Bennett J. Sequence analysis of human J chain. Amino terminal location of a disulfide bond linking the immunoglobulin heavy chain. Biochem Biophys Res Commun. 1976;73:92\u20137.","journal-title":"Biochem Biophys Res Commun"},{"key":"3023_CR26","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.bbrc.2019.02.051","volume":"511","author":"M Wortmann","year":"2019","unstructured":"Wortmann M, Skorubskaya E, Peters AS, Hakimi M, Bockler D, Dihlmann S. Necrotic cell debris induces a NF-kappaB-driven inflammasome response in vascular smooth muscle cells derived from abdominal aortic aneurysms (AAA-SMC). Biochem Biophys Res Commun. 2019;511:343\u20139.","journal-title":"Biochem Biophys Res Commun"},{"key":"3023_CR27","doi-asserted-by":"publisher","first-page":"737","DOI":"10.21873\/invivo.11533","volume":"33","author":"E Legaki","year":"2019","unstructured":"Legaki E, Klonaris C, Athanasiadis D, Patelis N, Sioziou A, Liakakos T, et al. DAB2IP expression in abdominal aortic aneurysm: EZH2 and mir-363-3p as potential mediators. Vivo. 2019;33:737\u201342.","journal-title":"Vivo"},{"key":"3023_CR28","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1093\/nar\/gkt896","volume":"42","author":"P Mathiyalagan","year":"2014","unstructured":"Mathiyalagan P, Okabe J, Chang L, Su Y, Du XJ, El-Osta A. The primary microRNA-208b interacts with Polycomb-group protein, Ezh2, to regulate gene expression in the heart. Nucleic Acids Res. 2014;42:790\u2013803.","journal-title":"Nucleic Acids Res"},{"key":"3023_CR29","doi-asserted-by":"crossref","first-page":"3206","DOI":"10.1111\/bph.14754","volume":"176","author":"J Liang","year":"2019","unstructured":"Liang J, Li Q, Cai W, Zhang X, Yang B, Li X, et al. Inhibition of polycomb repressor complex 2 ameliorates neointimal hyperplasia by suppressing trimethylation of H3K27 in vascular smooth muscle cells. Br J Pharmacol. 2019;176:3206\u201319.","journal-title":"Br J Pharmacol"},{"key":"3023_CR30","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.coviro.2011.11.004","volume":"1","author":"VA Rathinam","year":"2011","unstructured":"Rathinam VA, Fitzgerald KA. Cytosolic surveillance and antiviral immunity. Curr Opin Virol. 2011;1:455\u201362.","journal-title":"Curr Opin Virol"},{"key":"3023_CR31","doi-asserted-by":"publisher","first-page":"84","DOI":"10.3389\/fimmu.2018.00084","volume":"9","author":"YW Hu","year":"2018","unstructured":"Hu YW, Zhang J, Wu XM, Cao L, Nie P, Chang MX. TANK-binding kinase 1 (TBK1) isoforms negatively regulate type I interferon induction by inhibiting TBK1-IRF3 interaction and IRF3 phosphorylation. Front Immunol. 2018;9:84.","journal-title":"Front Immunol"},{"key":"3023_CR32","doi-asserted-by":"publisher","first-page":"30912","DOI":"10.1074\/jbc.M114.591966","volume":"289","author":"HP Moll","year":"2014","unstructured":"Moll HP, Lee A, Minussi DC, da Silva CG, Csizmadia E, Bhasin M, et al. A20 regulates atherogenic interferon (IFN)-gamma signaling in vascular cells by modulating basal IFNbeta levels. J Biol Chem. 2014;289:30912\u201324.","journal-title":"J Biol Chem"},{"key":"3023_CR33","doi-asserted-by":"publisher","first-page":"7477","DOI":"10.1074\/jbc.M410392200","volume":"280","author":"SP Gravel","year":"2005","unstructured":"Gravel SP, Servant MJ. Roles of an IkappaB kinase-related pathway in human cytomegalovirus-infected vascular smooth muscle cells: a molecular link in pathogen-induced proatherosclerotic conditions. J Biol Chem. 2005;280:7477\u201386.","journal-title":"J Biol Chem"},{"key":"3023_CR34","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1016\/j.lfs.2004.01.030","volume":"75","author":"T Imaizumi","year":"2004","unstructured":"Imaizumi T, Yagihashi N, Hatakeyama M, Yamashita K, Ishikawa A, Taima K, et al. Expression of retinoic acid-inducible gene-I in vascular smooth muscle cells stimulated with interferon-gamma. Life Sci. 2004;75:1171\u201380.","journal-title":"Life Sci"},{"key":"3023_CR35","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1038\/s41419-018-0264-z","volume":"9","author":"M Wang","year":"2018","unstructured":"Wang M, Guo C, Wang L, Luo G, Huang C, Li Y, et al. Long noncoding RNA GAS5 promotes bladder cancer cells apoptosis through inhibiting EZH2 transcription. Cell Death Dis. 2018;9:238.","journal-title":"Cell Death Dis"},{"key":"3023_CR36","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.molimm.2019.11.009","volume":"118","author":"X Zhu","year":"2020","unstructured":"Zhu X, Wang X, Wang Y, Zhao Y. Exosomal long non-coding RNA GAS5 suppresses Th1 differentiation and promotes Th2 differentiation via downregulating EZH2 and T-bet in allergic rhinitis. Mol Immunol. 2020;118:30\u20139.","journal-title":"Mol Immunol"},{"key":"3023_CR37","doi-asserted-by":"publisher","first-page":"2516","DOI":"10.1016\/j.bbadis.2019.05.022","volume":"1865","author":"R Tang","year":"2019","unstructured":"Tang R, Mei X, Wang YC, Cui XB, Zhang G, Li W, et al. LncRNA GAS5 regulates vascular smooth muscle cell cycle arrest and apoptosis via p53 pathway. Biochim Biophys Acta Mol Basis Dis. 2019;1865:2516\u201325.","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"3023_CR38","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1038\/s41590-019-0379-0","volume":"20","author":"H Lin","year":"2019","unstructured":"Lin H, Jiang M, Liu L, Yang Z, Ma Z, Liu S, et al. The long noncoding RNA Lnczc3h7a promotes a TRIM25-mediated RIG-I antiviral innate immune response. Nat Immunol. 2019;20:812\u201323.","journal-title":"Nat Immunol"},{"key":"3023_CR39","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1159\/000493967","volume":"50","author":"XD Tang","year":"2018","unstructured":"Tang XD, Zhang DD, Jia L, Ji W, Zhao YS. lncRNA AFAP1-AS1 promotes migration and invasion of non-small cell lung cancer via up-regulating IRF7 and the RIG-I-like receptor signaling pathway. Cell Physiol Biochem. 2018;50:179\u201395.","journal-title":"Cell Physiol Biochem"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-021-03023-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-021-03023-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-021-03023-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T16:58:23Z","timestamp":1699808303000},"score":1,"resource":{"primary":{"URL":"https:\/\/translational-medicine.biomedcentral.com\/articles\/10.1186\/s12967-021-03023-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["3023"],"URL":"https:\/\/doi.org\/10.1186\/s12967-021-03023-w","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]},"assertion":[{"value":"8 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was approved by the Ethics Committee of Xiangya Hospital and carried out in accordance with the Guide for the Care and Use of Laboratory animals published by the US National Institutes of Health. Extensive efforts were made to minimize the number and suffering of the included animals.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that there is no conflict of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"466"}}