{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:54:18Z","timestamp":1791161658008,"version":"4.1.0"},"reference-count":29,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,7,19]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Cardiac hypertrophy is an adaptive response to pressure overload aimed at maintaining cardiac function. However, prolonged hypertrophy significantly increases the risk of maladaptive cardiac remodeling and heart failure. Recent studies have implicated long noncoding RNAs in cardiac hypertrophy and cardiomyopathy, but their significance and mechanism(s) of action are not well understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We measured\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      RNA and H3K27ac levels in the hearts of dilated cardiomyopathy patients. We assessed the functional role of\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      in basal and surgical pressure-overload conditions using loss-of-function mice. Genome-wide transcriptome analysis revealed dysregulated genes and pathways. We labeled proteins in proximity to full-length lincRNA-p21 using a novel BioID2-based system. We immunoprecipitated lincRNA-p21-interacting proteins and performed cell fractionation, ChIP-seq (chromatin immunoprecipitation followed by sequencing), and co-immunoprecipitation to investigate molecular interactions and underlying mechanisms. We used GapmeR antisense oligonucleotides to evaluate the therapeutic potential of\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      inhibition in cardiac hypertrophy and associated heart failure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      was induced in mice and humans with cardiomyopathy. Global and cardiac-specific\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      knockout significantly suppressed pressure overload-induced ventricular wall thickening, stress marker elevation, and deterioration of cardiac function. Genome-wide transcriptome analysis and transcriptional network analysis revealed that\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      acts\n                      <jats:italic toggle=\"yes\">in trans<\/jats:italic>\n                      to stimulate the NFAT\/MEF2 (nuclear factor of activated T cells\/myocyte enhancer factor-2) pathway. Mechanistically, lincRNA-p21 is bound to the scaffold protein KAP1 (KRAB-associated protein-1).\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      cardiac-specific knockout suppressed stress-induced nuclear accumulation of KAP1, and KAP1 knockdown attenuated cardiac hypertrophy and NFAT activation. KAP1 positively regulates pathological hypertrophy by physically interacting with NFATC4 to promote the overactive status of NFAT\/MEF2 signaling. GapmeR antisense oligonucleotide depletion of lincRNA-p21 similarly inhibited cardiac hypertrophy and adverse remodeling, highlighting the therapeutic potential of inhibiting\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      These findings advance our understanding of the functional significance of stress-induced long noncoding RNA in cardiac hypertrophy and demonstrate the potential of\n                      <jats:italic toggle=\"yes\">lincRNA-p21<\/jats:italic>\n                      as a novel therapeutic target for cardiac hypertrophy and subsequent heart failure.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.123.323356","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T05:00:38Z","timestamp":1718168438000},"page":"434-449","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Therapeutic Inhibition of\n                    <i>LincRNA-p21<\/i>\n                    Protects Against Cardiac Hypertrophy"],"prefix":"10.1161","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0291-5314","authenticated-orcid":true,"given":"Yi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8480-0280","authenticated-orcid":true,"given":"Mingming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Department of Cardiology, Tangdu Hospital, The Fourth Military Medical University, Xi\u2019an, China (M.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China (R.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3830-485X","authenticated-orcid":true,"given":"Jing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5625-1330","authenticated-orcid":true,"given":"Qing","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Public Health, Xi\u2019an Jiaotong University, China (J. Lin)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haipeng","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Department of Critical Care and Emergency Medicine, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China (H.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8853-8379","authenticated-orcid":true,"given":"Huihui","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Beth Israel Deaconess Medical Center (H.H.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6754-9346","authenticated-orcid":true,"given":"Zhuomin","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Department of Cardiology (Z.L.), Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangpo","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0979-7100","authenticated-orcid":true,"given":"Xiaoran","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6200-2974","authenticated-orcid":true,"given":"Yao Wei","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Vascular Biology Program, Boston Children\u2019s Hospital (Y.W.L.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Vertex Pharmaceuticals, Vertex Cell and Genetic Therapy, Boston, MA (J. Liu)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9084-9328","authenticated-orcid":true,"given":"Feng","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1338-1124","authenticated-orcid":true,"given":"Hualin","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Department of Medical Ultrasound, Laboratory of Ultrasound Imaging Drug, West China Hospital, Sichuan University, Chengdu, China (H.Y.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5983-1496","authenticated-orcid":true,"given":"Nadya","family":"Dimitrova","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT (N.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7054-655X","authenticated-orcid":true,"given":"Zhan-Peng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Department of Cardiology, Center for Translational Medicine (Z.-P.H.), Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3626-9090","authenticated-orcid":true,"given":"John D.","family":"Mably","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine and USF Health Heart Institute, Department of Internal Medicine, University of South Florida, Tampa (J.D.M., D.-Z.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4551-8079","authenticated-orcid":true,"given":"William T.","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Harvard Stem Cell Institute, Harvard University, Cambridge, MA (W.T.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1774-6549","authenticated-orcid":true,"given":"Da-Zhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital (Y.W., M.Z., R.W., J. Lin, Q.M., H.G., Z.L., Y.C., X.Z., Y.W.L., J. Liu, F.X., H.Y., Z.-P.H., W.T.P., D.-Z.W.), Harvard Medical School, Boston, MA."},{"name":"Center for Regenerative Medicine and USF Health Heart Institute, Department of Internal Medicine, University of South Florida, Tampa (J.D.M., D.-Z.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199005313222203"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.physiol.65.092101.142243"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.07.007"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.003863"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.040"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.114.011675"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2014.165"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.04.025"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)81573-1"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9062004"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2012.12.016"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.06.020"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.07.050"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/gtc.12906"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110687"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E15-12-0844"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe8952"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.973302"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1315155110"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00487-06"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.08.032"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.254532.114"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.052384"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000120390.68287.BB"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000069211.82346.46"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(00)80027-5"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12859-018-2445-2"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI82423"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.123.323356","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T17:56:36Z","timestamp":1760982996000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.123.323356"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,19]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2024,7,19]]}},"alternative-id":["10.1161\/CIRCRESAHA.123.323356"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.123.323356","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,19]]},"assertion":[{"value":"2023-07-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-22","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}