{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T21:09:25Z","timestamp":1785186565538,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>The pathological changes of ubiquitination and deubiquitination following myocardial infarction (MI) and chronic heart failure (CHF) have been sparsely examined. We investigated the expression of muscle-specific E3 ubiquitin ligases and deubiquitinases in MI and CHF. Therefore, mice were assigned to coronary artery ligation for 3 days or 10 weeks as well as for sham operation (each n = 10). Expression of E3 ligases (MAFBX, MURF1, CHIP, ITCH, MDM2) and deubiquitinases (A20, CYLD, UCH-L1, USP14, USP19) was determined. After MI and in CHF, the mRNA expression of MURF1, CHIP and MDM2 (all p &lt; 0.05) was decreased. Protein expression analyses revealed that ITCH expression decreased in CHF (p = 0.01), whereas MDM2 expression increased in MI (p = 0.02) and decreased in CHF (p = 0.02). Except for USP19 mRNA expression that decreased at 3 days and 10 weeks (both p &lt; 0.01), the expression of other deubiquitinases remained unaffected after MI and CHF. The expression of myocardial E3 ligases is differentially regulated following MI, raising the question of whether an upstream regulation exists that is activated by MI for tissue protection or whether the downregulation of E3 ligases enables myocardial hypertrophy following MI.<\/jats:p>","DOI":"10.3390\/life11121430","type":"journal-article","created":{"date-parts":[[2021,12,19]],"date-time":"2021-12-19T20:37:27Z","timestamp":1639946247000},"page":"1430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Differential Regulation of Myocardial E3 Ligases and Deubiquitinases in Ischemic Heart Failure"],"prefix":"10.3390","volume":"11","author":[{"given":"Kristin","family":"Klaeske","sequence":"first","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Dix","sequence":"additional","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7955-7324","authenticated-orcid":false,"given":"Volker","family":"Adams","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular and Experimental Cardiology, Heart Center Dresden, TU Dresden, Fetscherstra\u00dfe 76, 01307 Dresden, Germany"},{"name":"Dresden Cardiovascular Research Institute and Core Laboratories GmbH, Bautzner Stra\u00dfe 122c, 01099 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalil","family":"Jawad","sequence":"additional","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Eifert","sequence":"additional","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Etz","sequence":"additional","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7449-9455","authenticated-orcid":false,"given":"Diyar","family":"Saeed","sequence":"additional","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Borger","sequence":"additional","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maja-Theresa","family":"Dieterlen","sequence":"additional","affiliation":[{"name":"Department for Cardiac Surgery, HELIOS Clinic, Heart Center, University Hospital Leipzig, Str\u00fcmpellstra\u00dfe 39, 04289 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1042\/CS20140663","article-title":"Circulating E3 ligases are novel and sensitive biomarkers for diagnosis of acute myocardial infarction","volume":"128","author":"Han","year":"2015","journal-title":"Clin. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1016\/j.bbrc.2016.08.100","article-title":"Ubiquitin-specific protease 14 regulates cardiac hypertrophy progression by increasing GSK-3\u03b2 phosphorylation","volume":"478","author":"Liu","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.yjmcc.2013.11.008","article-title":"The role of ubiquitin ligases in cardiac disease","volume":"71","author":"Willis","year":"2014","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1146\/annurev-biochem-061516-044916","article-title":"Mechanisms of Deubiquitinase Specificity and Regulation","volume":"86","author":"Mevissen","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.bbadis.2008.06.009","article-title":"The ubiquitin-proteasome system in cardiac dysfunction","volume":"1782","author":"Mearini","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4051","DOI":"10.1113\/JP273607","article-title":"Proteasome dysfunction in cardiomyopathies","volume":"595","author":"Gilda","year":"2017","journal-title":"J. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1152\/japplphysiol.00756.2014","article-title":"Diaphragm muscle weakness in mice is early-onset post-myocardial infarction and associated with elevated protein oxidation","volume":"118","author":"Bowen","year":"2015","journal-title":"J. Appl Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1016\/j.bbadis.2016.07.002","article-title":"Cardiac ubiquitin ligases: Their role in cardiac metabolism, autophagy, cardioprotection and therapeutic potential","volume":"1862","author":"Parry","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1172\/JCI66339","article-title":"Atrogin-1 deficiency promotes cardiomyopathy and premature death via impaired autophagy","volume":"124","author":"Zaglia","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"336","DOI":"10.3389\/fgene.2018.00336","article-title":"Emergence of Members of TRAF and DUB of Ubiquitin Proteasome System in the Regulation of Hypertrophic Cardiomyopathy","volume":"9","author":"Gupta","year":"2018","journal-title":"Front. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.cardiores.2006.10.026","article-title":"Myocardial expression of Murf-1 and MAFbx after induction of chronic heart failure: Effect on myocardial contractility","volume":"73","author":"Adams","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1097\/HJR.0b013e3282f3ec43","article-title":"Modulation of Murf-1 and MAFbx expression in the myocardium by physical exercise training","volume":"15","author":"Adams","year":"2008","journal-title":"Eur. J. Cardiovasc. Prev. Rehabil."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1161\/CIRCRESAHA.109.194928","article-title":"Cardiac muscle ring finger-1 increases susceptibility to heart failure in vivo","volume":"105","author":"Willis","year":"2009","journal-title":"Circ. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1093\/eurjhf\/hfq102","article-title":"Myocardial expression of FOXO3a-Atrogin-1 pathway in human heart failure","volume":"12","author":"Galasso","year":"2010","journal-title":"Eur. J. Heart Fail."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/mus.21293","article-title":"Atrogin-1, MuRF1, and FoXO, as well as phosphorylated GSK-3beta and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord-injured patients","volume":"40","author":"Senese","year":"2009","journal-title":"Muscle Nerve"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00395-009-0068-5","article-title":"Depressed expression of MuRF1 and MAFbx in areas remote of recent myocardial infarction: A mechanism contributing to myocardial remodeling?","volume":"105","author":"Conraads","year":"2010","journal-title":"Basic Res. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Sp\u00e4nig, S., Kellermann, K., Dieterlen, M.T., Noack, T., Lehmann, S., Borger, M.A., Garbade, J., Barac, Y.D., and Emrich, F. (2019). The Ubiquitin Proteasome System in Ischemic and Dilated Cardiomyopathy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246354"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8869","DOI":"10.1074\/jbc.M109.063321","article-title":"The ubiquitin ligase itch regulates apoptosis by targeting thioredoxin-interacting protein for ubiquitin-dependent degradation","volume":"285","author":"Zhang","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.cardfail.2019.01.017","article-title":"Ischemic Cardiomyopathy Affects the Thioredoxin System in the Human Myocardium","volume":"25","author":"Neidhardt","year":"2019","journal-title":"J. Card Fail."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.yjmcc.2011.10.023","article-title":"Back to your heart: Ubiquitin proteasome system-regulated signal transduction","volume":"52","author":"Portbury","year":"2012","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1007\/s11906-009-0069-7","article-title":"Seek and destroy: The ubiquitin-proteasome system in cardiac disease","volume":"11","author":"Schisler","year":"2009","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"320","DOI":"10.3389\/fcell.2019.00320","article-title":"Considering the Role of Murine Double Minute 2 in the Cardiovascular System?","volume":"7","author":"Lam","year":"2019","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1096\/fj.15-276964","article-title":"Phosphorylation of murine double minute-2 on Ser166 is downstream of VEGF-A in exercised skeletal muscle and regulates primary endothelial cell migration and FoxO gene expression","volume":"30","author":"Aiken","year":"2016","journal-title":"FASEB J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/978-94-017-9211-0_11","article-title":"Crosstalk between Mdm2, p53 and HIF1-\u03b1: Distinct responses to oxygen stress and implications for tumour hypoxia","volume":"85","author":"Robertson","year":"2014","journal-title":"Subcell Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1692","DOI":"10.1161\/CIRCRESAHA.109.214346","article-title":"Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury","volume":"106","author":"Naito","year":"2010","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1055\/s-2003-37149","article-title":"Age-related expression of p53, Mdm2, EGFR and Msh2 in glioblastoma multiforme","volume":"64","author":"Stark","year":"2003","journal-title":"Zentralbl. Neurochir."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"866","DOI":"10.15252\/embj.201593596","article-title":"USP19 modulates autophagy and antiviral immune responses by deubiquitinating Beclin-1","volume":"35","author":"Jin","year":"2016","journal-title":"EMBO J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10604","DOI":"10.1038\/s41598-020-67746-4","article-title":"Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78)","volume":"10","author":"Lei","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"795","DOI":"10.4161\/auto.7.7.15844","article-title":"BAG3 and friends: Co-chaperones in selective autophagy during aging and disease","volume":"7","author":"Behl","year":"2011","journal-title":"Autophagy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1593\/neo.121534","article-title":"p53-independent roles of MDM2 in NF-\u03baB signaling: Implications for cancer therapy, wound healing, and autoimmune diseases","volume":"14","author":"Thomasova","year":"2012","journal-title":"Neoplasia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1038\/ni.2157","article-title":"The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation","volume":"12","author":"Ahmed","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1161\/CIRCRESAHA.110.226928","article-title":"Multiple facets of NF-\u03baB in the heart: To be or not to NF-\u03baB","volume":"108","author":"Gordon","year":"2011","journal-title":"Circ. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1158\/1541-7786.MCR-10-0042","article-title":"Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways","volume":"8","author":"Ramabhadran","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1096\/fj.05-5249fje","article-title":"Human skeletal muscle atrophy in amyotrophic lateral sclerosis reveals a reduction in Akt and an increase in atrogin-1","volume":"20","author":"Vergani","year":"2006","journal-title":"FASEB J."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Brattelid, T., Winer, L.H., Levy, F.O., Liest\u00f8l, K., Sejersted, O.M., and Andersson, K.B. (2010). Reference gene alternatives to Gapdh in rodent and human heart failure gene expression studies. BMC Mol. Biol., 11.","DOI":"10.1186\/1471-2199-11-22"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.1249\/MSS.0000000000001016","article-title":"Exercise Training Prevents Diaphragm Contractile Dysfunction in Heart Failure","volume":"48","author":"Mangner","year":"2016","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1002\/jcsm.12448","article-title":"Small-molecule-mediated chemical knock-down of MuRF1\/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure","volume":"10","author":"Adams","year":"2019","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_38","unstructured":"(2020, December 12). Primer3web. Available online: http:\/\/primer3.ut.ee."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1111\/1440-1681.13236","article-title":"Impact of Custodiol-N cardioplegia on acute kidney injury after cardiopulmonary bypass","volume":"47","author":"Feirer","year":"2020","journal-title":"Clin. Exp. Pharmacol. Physiol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/12\/1430\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:51:26Z","timestamp":1760169086000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/11\/12\/1430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,18]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["life11121430"],"URL":"https:\/\/doi.org\/10.3390\/life11121430","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,18]]}}}