{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:50:29Z","timestamp":1789757429139,"version":"4.0.1"},"reference-count":46,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T00:00:00Z","timestamp":1697673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"GIF (Germany Israeli Foundation)","award":["I-2347-201.2\/24"],"award-info":[{"award-number":["I-2347-201.2\/24"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study investigated modifications to the ubiquitin proteasome system (UPS) in a mouse model of type 2 diabetes mellitus (T2DM) and their relationship to heart complications. db\/db mice heart tissues were compared with WT mice tissues using RNA sequencing, qRT-PCR, and protein analysis to identify cardiac UPS modifications associated with diabetes. The findings unveiled a distinctive gene profile in the hearts of db\/db mice with decreased levels of nppb mRNA and increased levels of Myh7, indicating potential cardiac dysfunction. The mRNA levels of USP18 (deubiquitinating enzyme), PSMB8, and PSMB9 (proteasome \u03b2-subunits) were down-regulated in db\/db mice, while the mRNA levels of RNF167 (E3 ligase) were increased. Corresponding LMP2 and LMP7 proteins were down-regulated in db\/db mice, and RNF167 was elevated in Adult diabetic mice. The reduced expression of LMP2 and LMP7, along with increased RNF167 expression, may contribute to the future cardiac deterioration commonly observed in diabetes. This study enhances our understanding of UPS imbalances in the hearts of diabetic mice and raises questions about the interplay between the UPS and other cellular processes, such as autophagy. Further exploration in this area could provide valuable insights into the mechanisms underlying diabetic heart complications and potential therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms242015376","type":"journal-article","created":{"date-parts":[[2023,10,19]],"date-time":"2023-10-19T11:46:26Z","timestamp":1697715986000},"page":"15376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Ubiquitin Proteasome System Role in Diabetes-Induced Cardiomyopathy"],"prefix":"10.3390","volume":"24","author":[{"given":"Ortal","family":"Nahum-Ankonina","sequence":"first","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efrat","family":"Kurtzwald-Josefson","sequence":"additional","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Ciechanover","sequence":"additional","affiliation":[{"name":"The Ruth & Bruce Rappaport Faculty of Medicine, Technion\u2014Israel Institute of Technology, Haifa 3109601, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maayan","family":"Waldman","sequence":"additional","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orna","family":"Shwartz-Rohaker","sequence":"additional","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Hochhauser","sequence":"additional","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6887-815X","authenticated-orcid":false,"given":"Sam J.","family":"Meyer","sequence":"additional","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Aravot","sequence":"additional","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Phillip","sequence":"additional","affiliation":[{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"The Division of Endocrinology, Schneider Medical Center, Petach-Tikva 4920235, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4688-2358","authenticated-orcid":false,"given":"Yaron D.","family":"Barac","sequence":"additional","affiliation":[{"name":"The Division of Cardiovascular and Thoracic Surgery, Rabin Medical Center, Petach-Tikva 4941492, Israel"},{"name":"Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.2522\/ptj.20080020","article-title":"Epidemiology of diabetes and diabetes-related complications","volume":"88","author":"Deshpande","year":"2008","journal-title":"Phys. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1161\/CIRCRESAHA.118.311371","article-title":"Heart Failure in Type 2 Diabetes Mellitus","volume":"124","author":"Kenny","year":"2019","journal-title":"Circ. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e3213","DOI":"10.1002\/dmrr.3213","article-title":"Probiotics for the treatment of type 2 diabetes: A review of randomized controlled trials","volume":"36","author":"Tiderencel","year":"2020","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1161\/CIRCULATIONAHA.119.042685","article-title":"Heart Failure Risk Stratification and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Type 2 Diabetes Mellitus","volume":"140","author":"Berg","year":"2019","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s11154-010-9131-7","article-title":"Diabetic cardiomyopathy, causes and effects","volume":"11","author":"Boudina","year":"2010","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.4239\/wjd.v4.i5.177","article-title":"Diabetic cardiomyopathy: Pathophysiology, diagnostic evaluation and management","volume":"4","author":"Pappachan","year":"2013","journal-title":"World J. Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s12933-015-0263-7","article-title":"Coronary microvascular function is independently associated with left ventricular filling pressure in patients with type 2 diabetes mellitus","volume":"14","author":"Kawata","year":"2015","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/sj.onc.1207973","article-title":"The anaphase-promoting complex: A key factor in the regulation of cell cycle","volume":"24","author":"Castro","year":"2005","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1002\/(SICI)1521-1878(200005)22:5<442::AID-BIES6>3.0.CO;2-Q","article-title":"Ubiquitin-mediated proteolysis: Biological regulation via destruction","volume":"22","author":"Ciechanover","year":"2000","journal-title":"Bioessays"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nrm731","article-title":"Deadly encounter: Ubiquitin meets apoptosis","volume":"3","author":"Jesenberger","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/nrm1552","article-title":"Proteolysis: From the lysosome to ubiquitin and the proteasome","volume":"6","author":"Ciechanover","year":"2005","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1152\/physrev.00027.2001","article-title":"The ubiquitin-proteasome proteolytic pathway: Destruction for the sake of construction","volume":"82","author":"Glickman","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1042\/BJ20100985","article-title":"E2s: Structurally economical and functionally replete","volume":"433","author":"Wenzel","year":"2011","journal-title":"Biochem. J."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.ymthe.2019.09.025","article-title":"Ablation of Immunoproteasome beta5i Subunit Suppresses Hypertensive Retinopathy by Blocking ATRAP Degradation in Mice","volume":"28","author":"Wang","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/S0300-9084(01)01244-5","article-title":"The unfolding of substrates and ubiquitin-independent protein degradation by proteasomes","volume":"83","author":"Benaroudj","year":"2001","journal-title":"Biochimie"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.molimm.2017.01.019","article-title":"Immunoproteasome subunit deficiency has no influence on the canonical pathway of NF-kappaB activation","volume":"83","author":"Bitzer","year":"2017","journal-title":"Mol. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"E592","DOI":"10.1152\/ajpendo.00277.2013","article-title":"Effects of insulin resistance on skeletal muscle growth and exercise capacity in type 2 diabetic mouse models","volume":"306","author":"Ostler","year":"2014","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1093\/cvr\/cvp217","article-title":"Multiple cardiac proteasome subtypes differ in their susceptibility to proteasome inhibitors","volume":"85","author":"Meiners","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"H146","DOI":"10.1152\/ajpheart.00583.2005","article-title":"Myocardial infarction and heart failure in the db\/db diabetic mouse","volume":"290","author":"Greer","year":"2006","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1113\/EP085091","article-title":"Regulation of B-type natriuretic peptide synthesis by insulin in obesity in male mice","volume":"101","author":"Zhang","year":"2016","journal-title":"Exp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s10974-017-9486-4","article-title":"Intrinsic MYH7 expression regulation contributes to tissue level allelic imbalance in hypertrophic cardiomyopathy","volume":"38","author":"Montag","year":"2017","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1161\/CIRCULATIONAHA.109.904557","article-title":"Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies","volume":"121","author":"Predmore","year":"2010","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"F548","DOI":"10.1152\/ajprenal.00509.2020","article-title":"Lipotoxicity dysregulates the immunoproteasome in podocytes and kidneys in type 2 diabetes","volume":"320","author":"Lee","year":"2021","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.yjmcc.2007.12.009","article-title":"Upregulation of myocardial 11S-activated proteasome in experimental hyperglycemia","volume":"44","author":"Powell","year":"2008","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/B978-0-12-397863-9.00009-2","article-title":"The ubiquitin-proteasome system and cardiovascular disease","volume":"109","author":"Powell","year":"2012","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.trsl.2018.09.003","article-title":"Proteasome biology and therapeutics in cardiac diseases","volume":"205","author":"Shukla","year":"2019","journal-title":"Transl. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Peris-Moreno, D., Taillandier, D., and Polge, C. (2020). MuRF1\/TRIM63, Master Regulator of Muscle Mass. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186663"},{"key":"ref_29","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_30","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1007\/s10863-014-9549-9","article-title":"MuRF1 activity is present in cardiac mitochondria and regulates reactive oxygen species production in vivo","volume":"46","author":"Mattox","year":"2014","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_31","first-page":"396","article-title":"Seek and destroy: The ubiquitin-proteasome system in cardiac disease","volume":"6","author":"Schisler","year":"2009","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_32","first-page":"36","article-title":"The ubiquitin ligase MuRF1 regulates PPAR\u03b1 activity in the heart by enhancing nuclear export via monoubiquitination","volume":"15","author":"Liao","year":"2015","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1038\/385737a0","article-title":"Editing of ubiquitin conjugates by an isopeptidase in the 26S proteasome","volume":"385","author":"Lam","year":"1997","journal-title":"Nature"},{"key":"ref_34","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_35","first-page":"133","article-title":"Naturally occurring and tumor-associated variants of RNF167 promote lysosomal exocytosis and plasma membrane resealing","volume":"11","author":"Nair","year":"2020","journal-title":"J. Cell Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1042\/BJ20131067","article-title":"Tumour-associated mutations of PA-TM-RING ubiquitin ligases RNF167\/RNF13 identify the PA domain as a determinant for endosomal localization","volume":"459","author":"Yamazaki","year":"2014","journal-title":"Biochem. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19426","DOI":"10.1073\/pnas.1217477109","article-title":"Ubiquitin ligase RNF167 regulates AMPA receptor-mediated synaptic transmission","volume":"109","author":"Lussier","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Govoruskina, N., Jakovljevic, V., Zivkovic, V., Milosavljevic, I., Jeremic, J., Bradic, J., Bolevich, S., Omarov, I.A., Djuric, D., and Radonjic, K. (2020). The Role of Cardiac N-Methyl-D-Aspartate Receptors in Heart Conditioning-Effects on Heart Function and Oxidative Stress. Biomolecules, 10.","DOI":"10.3390\/biom10071065"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.healun.2017.02.012","article-title":"The ubiquitin-proteasome system: A potential therapeutic target for heart failure","volume":"36","author":"Barac","year":"2017","journal-title":"J. Heart Lung Transplant."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3389\/fnmol.2017.00347","article-title":"Regulation of AMPA Receptor Trafficking by Protein Ubiquitination","volume":"26","author":"Widagdo","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2528","DOI":"10.1093\/hmg\/ddv017","article-title":"The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1\/PARK2 pathway","volume":"24","author":"Gao","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.3389\/fphys.2018.01575","article-title":"Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients","volume":"9","author":"Uthman","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lloyd-Evans, E., and Waller-Evans, H. (2020). Lysosomal Ca2+ Homeostasis and Signaling in Health and Disease. Cold Spring Harb. Perspect. Biol., 12.","DOI":"10.1101\/cshperspect.a035311"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.ijcard.2018.08.070","article-title":"Endoplasmic reticulum stress impairs cardiomyocyte contractility through JNK-dependent upregulation of BNIP3","volume":"272","author":"Bozi","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1161\/HYPERTENSIONAHA.116.07562","article-title":"Novel Protective Role for Ubiquitin-Specific Protease 18 in Pathological Cardiac Remodeling","volume":"68","author":"Ying","year":"2016","journal-title":"Hypertension"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kasacka, I., Piotrowska, \u017b., Niezgoda, M., Lewandowska, A., and \u0141ebkowski, W. (2020). Ageing-related changes in the levels of beta-catenin, CacyBP\/SIP, galectin-3 and immunoproteasome subunit LMP7 in the heart of men. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229462"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:09:58Z","timestamp":1760130598000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/20\/15376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,19]]},"references-count":46,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms242015376"],"URL":"https:\/\/doi.org\/10.3390\/ijms242015376","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,19]]}}}