{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T10:24:45Z","timestamp":1769077485899,"version":"3.49.0"},"reference-count":37,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T00:00:00Z","timestamp":1634083200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010447","name":"Deutsches Zentrum f\u00fcr Herz-Kreislaufforschung","doi-asserted-by":"publisher","award":["na"],"award-info":[{"award-number":["na"]}],"id":[{"id":"10.13039\/100010447","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital heart disease (CHD) is one of the most common birth defects in humans, present in around 40% of newborns with Down\u2019s syndrome (DS). The SH3 domain-binding glutamic acid-rich (SH3BGR) gene, which maps to the DS region, belongs to a gene family encoding a cluster of small thioredoxin-like proteins sharing SH3 domains. Although its expression is confined to the cardiac and skeletal muscle, the physiological role of SH3BGR in the heart is poorly understood. Interestingly, we observed a significant upregulation of SH3BGR in failing hearts of mice and human patients with hypertrophic cardiomyopathy. Along these lines, the overexpression of SH3BGR exhibited a significant increase in the expression of hypertrophic markers (Nppa and Nppb) and increased cell surface area in neonatal rat ventricular cardiomyocytes (NRVCMs), whereas its knockdown attenuated cellular hypertrophy. Mechanistically, using serum response factor (SRF) response element-driven luciferase assays in the presence or the absence of RhoA or its inhibitor, we found that the pro-hypertrophic effects of SH3BGR are mediated via the RhoA\u2013SRF axis. Furthermore, SH3BGR knockdown resulted in the induction of apoptosis and reduced cell viability in NRVCMs via apoptotic Hippo\u2013YAP signaling. Taking these results together, we here show that SH3BGR is vital for maintaining cytoskeletal integrity and cellular viability in NRVCMs through its modulation of the SRF\/YAP signaling pathways.<\/jats:p>","DOI":"10.3390\/ijms222011042","type":"journal-article","created":{"date-parts":[[2021,10,13]],"date-time":"2021-10-13T21:36:15Z","timestamp":1634160975000},"page":"11042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["SH3-Binding Glutamic Acid Rich-Deficiency Augments Apoptosis in Neonatal Rat Cardiomyocytes"],"prefix":"10.3390","volume":"22","author":[{"given":"Anushka","family":"Deshpande","sequence":"first","affiliation":[{"name":"Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany"},{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 24105 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankush","family":"Borlepawar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 24105 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Rosskopf","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derk","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg\/Kiel\/L\u00fcbeck, 24105 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Frey","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg\/Mannheim, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2630-9754","authenticated-orcid":false,"given":"Ashraf Yusuf","family":"Rangrez","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany"},{"name":"Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, 69120 Heidelberg, Germany"},{"name":"DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg\/Mannheim, 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"ref_1","first-page":"17","article-title":"Down\u2019s syndrome","volume":"28","author":"Crawford","year":"2016","journal-title":"Nurs. Child. Young People"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41572-019-0143-7","article-title":"Down syndrome","volume":"6","author":"Antonarakis","year":"2020","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"287","DOI":"10.5830\/CVJA-2016-019","article-title":"Congenital heart disease and Down syndrome: Various aspects of a confirmed association","volume":"27","author":"Benhaourech","year":"2016","journal-title":"Cardiovasc. J. Afr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12929-015-0138-y","article-title":"Down syndrome: An insight of the disease","volume":"22","author":"Asim","year":"2015","journal-title":"J. Biomed. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1432-1033.1995.tb20430.x","article-title":"The MADS-box family of transcription factors","volume":"229","author":"Shore","year":"1995","journal-title":"Eur. J. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1038\/labinvest.2010.104","article-title":"Role of serum response factor in the pathogenesis of disease","volume":"90","author":"Miano","year":"2010","journal-title":"Lab. Investig. A J. Tech. Methods Pathol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jjcc.2011.01.002","article-title":"Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides","volume":"57","author":"Nishikimi","year":"2011","journal-title":"J. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1083\/jcb.201303052","article-title":"Dysbindin is a potent inducer of RhoA-SRF-mediated cardiomyocyte hypertrophy","volume":"203","author":"Rangrez","year":"2013","journal-title":"J. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2361","DOI":"10.1101\/gad.304501.117","article-title":"Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics","volume":"31","author":"Foster","year":"2017","journal-title":"Genes Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.devcel.2018.03.019","article-title":"Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development","volume":"45","author":"Xiao","year":"2018","journal-title":"Dev. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1038\/s41569-018-0063-3","article-title":"The Hippo pathway in the heart: Pivotal roles in development, disease, and regeneration","volume":"15","author":"Wang","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1161\/CIRCRESAHA.116.303311","article-title":"The hippo pathway in heart development, regeneration, and diseases","volume":"116","author":"Zhou","year":"2015","journal-title":"Circ. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.molcel.2014.04.007","article-title":"Mst1 promotes cardiac myocyte apoptosis through phosphorylation and inhibition of Bcl-xL","volume":"54","author":"Matsuda","year":"2014","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1161\/CIRCRESAHA.116.308586","article-title":"NF2 Activates Hippo Signaling and Promotes Ischemia\/Reperfusion Injury in the Heart","volume":"119","author":"Matsuda","year":"2016","journal-title":"Circ. Res."},{"key":"ref_15","first-page":"1511","article-title":"Regulation of Myocardial Cell Growth and Death by the Hippo Pathway","volume":"80","author":"Ikeda","year":"2016","journal-title":"Circ. J. Off. J. Jpn. Circ. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3977","DOI":"10.1074\/jbc.M112.436311","article-title":"Yes-associated protein isoform 1 (Yap1) promotes cardiomyocyte survival and growth to protect against myocardial ischemic injury","volume":"288","author":"Yang","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1038\/ncomms4315","article-title":"A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response","volume":"5","author":"Shao","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11317","DOI":"10.1038\/ncomms11317","article-title":"Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression","volume":"7","author":"Eden","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4128","DOI":"10.1074\/jbc.M115.689620","article-title":"Myozap Deficiency Promotes Adverse Cardiac Remodeling via Differential Regulation of Mitogen-activated Protein Kinase\/Serum-response Factor and beta-Catenin\/GSK-3beta Protein Signaling","volume":"291","author":"Rangrez","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.yjmcc.2014.03.016","article-title":"Mice with cardiac-restricted overexpression of Myozap are sensitized to biomechanical stress and develop a protein-aggregate-associated cardiomyopathy","volume":"72","author":"Frank","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1161\/CIRCRESAHA.109.213256","article-title":"Myozap, a novel intercalated disc protein, activates serum response factor-dependent signaling and is required to maintain cardiac function in vivo","volume":"106","author":"Seeger","year":"2010","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"15180","DOI":"10.1074\/jbc.M117.786764","article-title":"The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling","volume":"292","author":"Dierck","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s004390050377","article-title":"Cloning a new human gene from chromosome 21q22.3 encoding a glutamic acid-rich protein expressed in heart and skeletal muscle","volume":"99","author":"Scartezzini","year":"1997","journal-title":"Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/S0925-4773(99)00253-1","article-title":"Developmental expression of the SH3BGR gene, mapping to the Down syndrome heart critical region","volume":"90","author":"Egeo","year":"2000","journal-title":"Mech. Dev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00439-004-1088-8","article-title":"Heart morphogenesis is not affected by overexpression of the Sh3bgr gene mapping to the Down syndrome heart critical region","volume":"114","author":"Sandri","year":"2004","journal-title":"Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S0378-1119(02)00602-9","article-title":"The identification of a novel human homologue of the SH3 binding glutamic acid-rich (SH3BGR) gene establishes a new family of highly conserved small proteins related to Thioredoxin Superfamily","volume":"291","author":"Mazzocco","year":"2002","journal-title":"Gene"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e2008861118","DOI":"10.1073\/pnas.2008861118","article-title":"Sarcomeres regulate murine cardiomyocyte maturation through MRTF-SRF signaling","volume":"118","author":"Guo","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"baw100","DOI":"10.1093\/database\/baw100","article-title":"The harmonizome: A collection of processed datasets gathered to serve and mine knowledge about genes and proteins","volume":"2016","author":"Rouillard","year":"2016","journal-title":"Database"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s12929-021-00730-w","article-title":"RhoA: A dubious molecule in cardiac pathophysiology","volume":"28","author":"Kilian","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4161\/sgtp.18960","article-title":"Control of Rho GTPase function by BAR-domains","volume":"3","author":"Hordijk","year":"2012","journal-title":"Small GTPases"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"102596","DOI":"10.1016\/j.ebiom.2019.12.005","article-title":"SH3BGRL2 inhibits growth and metastasis in clear cell renal cell carcinoma via activating hippo\/TEAD1-Twist1 pathway","volume":"51","author":"Yin","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1006\/bbrc.1997.7816","article-title":"High-resolution physical map and identification of potentially regulatory sequences of the human SH3BGR located in the Down syndrome chromosomal region","volume":"241","author":"Bergonon","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1006\/bbrc.2001.5169","article-title":"A novel human homologue of the SH3BGR gene encodes a small protein similar to Glutaredoxin 1 of Escherichia coli","volume":"285","author":"Mazzocco","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1006\/bbrc.1998.8763","article-title":"Identification and characterization of a new human gene encoding a small protein with high homology to the proline-rich region of the SH3BGR gene","volume":"247","author":"Egeo","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s12031-011-9702-4","article-title":"Signal transducer and activator of transcription 2 (STAT2) metabolism coupling postmitotic outgrowth to visual and sound perception network in human left cerebrum by biocomputation","volume":"47","author":"Wang","year":"2012","journal-title":"J. Mol. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1038\/sj.onc.1209107","article-title":"The suppression of SH3BGRL is important for v-Rel-mediated transformation","volume":"25","author":"Majid","year":"2006","journal-title":"Oncogene"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"10180","DOI":"10.1074\/jbc.M116.752543","article-title":"TRIM24 protein promotes and TRIM32 protein inhibits cardiomyocyte hypertrophy via regulation of dysbindin protein levels","volume":"292","author":"Borlepawar","year":"2017","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11042\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:12:45Z","timestamp":1760166765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11042"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,13]]},"references-count":37,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222011042"],"URL":"https:\/\/doi.org\/10.3390\/ijms222011042","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,13]]}}}