{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T11:46:12Z","timestamp":1792842372517,"version":"4.5.0"},"reference-count":58,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T00:00:00Z","timestamp":1728604800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2024,10,11]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      Hypertrophic cardiomyopathy (HCM) is the most common cardiac genetic disorder caused by sarcomeric gene variants and associated with left ventricular hypertrophy and diastolic dysfunction. The role of the microtubule network has recently gained interest with the findings that microtubule detyrosination (dTyr-MT) is markedly elevated in heart failure. Acute reduction of dTyr-MT by inhibition of the detyrosinase (VASH [vasohibin]\/SVBP [small VASH-binding protein] complex) or activation of the tyrosinase (TTL [tubulin tyrosine ligase]) markedly improved contractility and reduced stiffness in human failing cardiomyocytes and thus posed a new perspective for HCM treatment. In this study, we tested the impact of chronic tubulin tyrosination in an HCM mouse model (\n                      <jats:italic toggle=\"yes\">Mybpc3<\/jats:italic>\n                      knock-in), in human HCM cardiomyocytes, and in SVBP-deficient human engineered heart tissues (EHTs).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>Adeno-associated virus serotype 9\u2013mediated TTL transfer was applied in neonatal wild-type rodents, in 3-week-old knock-in mice, and in HCM human induced pluripotent stem cell\u2013derived cardiomyocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>We show (1) TTL for 6 weeks dose dependently reduced dTyr-MT and improved contractility without affecting cytosolic calcium transients in wild-type cardiomyocytes; (2) TTL for 12 weeks reduced the abundance of dTyr-MT in the myocardium, improved diastolic filling, compliance, cardiac output, and stroke volume in knock-in mice; (3) TTL for 10 days normalized cell area in HCM human induced pluripotent stem cell\u2013derived cardiomyocytes; (4) TTL overexpression activated transcription of tubulins and other cytoskeleton components but did not significantly impact the proteome in knock-in mice; (5) SVBP-deficient EHTs exhibited reduced dTyr-MT levels, higher force, and faster relaxation than TTL-deficient and wild-type EHTs. RNA sequencing and mass spectrometry analysis revealed distinct enrichment of cardiomyocyte components and pathways in SVBP-deficient versus TTL-deficient EHTs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>This study provides the first proof of concept that chronic activation of tubulin tyrosination in HCM mice and in human EHTs improves heart function and holds promise for targeting the nonsarcomeric cytoskeleton in heart disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.124.324387","type":"journal-article","created":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T05:00:32Z","timestamp":1726462832000},"page":"910-932","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":36,"title":["Chronic Activation of Tubulin Tyrosination Improves Heart Function"],"prefix":"10.1161","volume":"135","author":[{"given":"Niels","family":"Pietsch","sequence":"first","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology (N.P., B.G., E.K., G.M., S.S., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, Germany (N.P., D.W., G.M., S.S., D.L., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina Y.","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (C.Y.C., M.A.C., B.L.P.)."},{"name":"Now with Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA (C.Y.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Kupsch","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart and Vascular Center (S.K., L.B., D.W., D.L.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"Now with Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, Germany (S.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8240-2270","authenticated-orcid":true,"given":"Lucas","family":"Bacmeister","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart and Vascular Center (S.K., L.B., D.W., D.L.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"Now with Faculty of Medicine, Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Germany (L.B., D.W., D.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Geertz","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology (N.P., B.G., E.K., G.M., S.S., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7064-9487","authenticated-orcid":true,"given":"Marisol","family":"Herrera-Rivero","sequence":"additional","affiliation":[{"name":"Department of Genetic Epidemiology, Institute of Human Genetics, University of M\u00fcnster, Germany (M.H.-R.)."},{"name":"Joint Institute for Individualisation in a Changing Environment, University of M\u00fcnster and Bielefeld University, M\u00fcnster, Germany (M.H.-R.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-0381","authenticated-orcid":true,"given":"Bente","family":"Siebels","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometric Proteomics (B.S., H.V., H.S.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Vo\u00df","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometric Proteomics (B.S., H.V., H.S.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Kr\u00e4mer","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology (N.P., B.G., E.K., G.M., S.S., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5676-9850","authenticated-orcid":true,"given":"Ingke","family":"Braren","sequence":"additional","affiliation":[{"name":"Vector Facility, Department of Experimental Pharmacology and Toxicology (I.B.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7542-1956","authenticated-orcid":true,"given":"Dirk","family":"Westermann","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart and Vascular Center (S.K., L.B., D.W., D.L.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"Now with Faculty of Medicine, Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Germany (L.B., D.W., D.L.)."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, Germany (N.P., D.W., G.M., S.S., D.L., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-7036","authenticated-orcid":true,"given":"Hartmut","family":"Schl\u00fcter","sequence":"additional","affiliation":[{"name":"Section Mass Spectrometric Proteomics (B.S., H.V., H.S.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Mearini","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology (N.P., B.G., E.K., G.M., S.S., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, Germany (N.P., D.W., G.M., S.S., D.L., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8329-6198","authenticated-orcid":true,"given":"Saskia","family":"Schlossarek","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology (N.P., B.G., E.K., G.M., S.S., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, Germany (N.P., D.W., G.M., S.S., D.L., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-5788","authenticated-orcid":true,"given":"Jolanda","family":"van der Velden","sequence":"additional","affiliation":[{"name":"Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands (J.v.d.V.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Caporizzo","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (C.Y.C., M.A.C., B.L.P.)."},{"name":"Now with Department of Molecular Physiology and Biophysics, University of Vermont Larner College of Medicine, Burlington, VT (M.A.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5477-769X","authenticated-orcid":true,"given":"Diana","family":"Lindner","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Heart and Vascular Center (S.K., L.B., D.W., D.L.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"Now with Faculty of Medicine, Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, University of Freiburg, Germany (L.B., D.W., D.L.)."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, Germany (N.P., D.W., G.M., S.S., D.L., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3696-9131","authenticated-orcid":true,"given":"Benjamin L.","family":"Prosser","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA (C.Y.C., M.A.C., B.L.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-5820","authenticated-orcid":true,"given":"Lucie","family":"Carrier","sequence":"additional","affiliation":[{"name":"Department of Experimental Pharmacology and Toxicology (N.P., B.G., E.K., G.M., S.S., L.C.), University Medical Center Hamburg-Eppendorf, Hamburg, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck, Germany (N.P., D.W., G.M., S.S., D.L., L.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2020.10.003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf0659"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.120.007022"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.12.006"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1177\/1535370219868960"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00692-y"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-062421-040656"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0046-2"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.119.315947"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.201251"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2012.03.009"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1038"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2021.102489"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2009.223"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/hgtb.2013.131"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2013.31"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201202168"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6515"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9526"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2018.09.019"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky354"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy249"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201911115"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00534.2021"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells11172745"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmccpl.2023.100050"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.138"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1721635115"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2019.00036"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aao4165"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/s0008-6363(03)00328-6"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1080\/19336918.2017.1386822"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu170"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0201-4"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp352"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu638"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz369"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41596-018-0082-x"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3901"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-022-00962-3"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn6020"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCHEARTFAILURE.117.004140"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1242\/bio.052381"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.837486"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.158774"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0180064"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2016.03.009"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat1199"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000126898.95550.31"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201210837"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2013.07.011"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2016.04.006"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adm8842"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2017.05.008"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1038\/s44161-023-00370-3"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.11.001"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.124.324387","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T16:05:53Z","timestamp":1748534753000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.124.324387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,11]]},"references-count":58,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,10,11]]}},"alternative-id":["10.1161\/CIRCRESAHA.124.324387"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.124.324387","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.05.25.542365","asserted-by":"object"}]},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,11]]},"assertion":[{"value":"2024-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-28","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}