{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:57:37Z","timestamp":1785430657927,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,30]]},"group-title":"Biochemistry","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T00:00:00Z","timestamp":1777507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["ZIA HL000225"],"award-info":[{"award-number":["ZIA HL000225"]}],"id":[{"id":"https:\/\/ror.org\/023ny1p48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  CaMKII\u03b4 is the dominant isozyme of Ca\n                  <jats:sup>2+<\/jats:sup>\n                  \/calmodulin-dependent protein kinase II in the heart. Under certain pathological conditions, it can be oxidized, causing a constitutive activation that can lead to cardiac failure. We recently showed that, in purified CaMKII\u03b4 exposed to oxidative conditions, a disulfide link formed between Cys273 and Cys290 causes this autonomous activation. Cys273 has a low pKa that facilitates the oxidation of its thiol to a sulfenic acid at physiological pH. Does this matter\n                  <jats:italic>in vivo<\/jats:italic>\n                  ? To answer that question, we created a transgenic mouse with Cys273 mutated to serine (CaMKII\u03b4\n                  <jats:sup>C273S<\/jats:sup>\n                  ) to prevent disulfide formation. We conducted a detailed assessment of cardiac function at rest and in a dobutamine stress test. We found that the CaMKII\u03b4 Cys273Ser mutation does not have deleterious effects on cardiac physiology. Then, we assessed whether the mutation would protect the heart from ischemia-reperfusion in the Langendorff model. The CaMKII\u03b4\n                  <jats:sup>C273S<\/jats:sup>\n                  mouse had improved cardiac function and decreased infarct size compared to the wild-type mouse. We conclude that blocking disulfide formation at Cys273 protects the heart against ischemia-reperfusion injury. Drugs that specifically target Cys 273 may be therapeutic in human cardiac disease.\n                <\/jats:p>","DOI":"10.64898\/2026.04.27.721066","type":"posted-content","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T14:35:19Z","timestamp":1777559719000},"source":"Crossref","is-referenced-by-count":0,"title":["Mutation of a single cysteine in CaMKII\u03b4 protects the heart from ischemia-reperfusion Injury"],"prefix":"10.64898","author":[{"given":"Nath\u00e1lia","family":"Rocco-Machado","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry, National Heart, Lung and Blood Institute, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhui","family":"Sun","sequence":"additional","affiliation":[{"name":"Cardiac Physiology Lab, Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Murine Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle A.","family":"Springer","sequence":"additional","affiliation":[{"name":"Murine Phenotyping Core, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Transgenic Core, National Heart, Lung, and Blood Institute, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Murphy","sequence":"additional","affiliation":[{"name":"Cardiac Physiology Lab, Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney L.","family":"Levine","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, National Heart, Lung and Blood Institute, Bethesda, Maryland, United States of America"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026050501300524000_2026.04.27.721066v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra071667"},{"key":"2026050501300524000_2026.04.27.721066v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-394309-5.00006-7"},{"key":"2026050501300524000_2026.04.27.721066v1.3","doi-asserted-by":"publisher","DOI":"10.1159\/000489241"},{"key":"2026050501300524000_2026.04.27.721066v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.09.086"},{"key":"2026050501300524000_2026.04.27.721066v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.02.048"},{"key":"2026050501300524000_2026.04.27.721066v1.6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.003313"},{"key":"2026050501300524000_2026.04.27.721066v1.7","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.117.005682"},{"key":"2026050501300524000_2026.04.27.721066v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102579"},{"key":"2026050501300524000_2026.04.27.721066v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2004.11.002"},{"key":"2026050501300524000_2026.04.27.721066v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2016.12.007"},{"key":"2026050501300524000_2026.04.27.721066v1.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707083200"},{"key":"2026050501300524000_2026.04.27.721066v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.11.005"},{"key":"2026050501300524000_2026.04.27.721066v1.13","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813013106"},{"key":"2026050501300524000_2026.04.27.721066v1.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1816521116"},{"key":"2026050501300524000_2026.04.27.721066v1.15","unstructured":"Guide for the Care and Use of Laboratory Animals. The National Academies Collection: Reports funded by National Institutes of Health. 8th ed. Washington (DC) 2011."},{"key":"2026050501300524000_2026.04.27.721066v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.04.025"},{"issue":"11","key":"2026050501300524000_2026.04.27.721066v1.17","first-page":"e264","article-title":"Off-target Effects in CRISPR\/Cas9-mediated Genome Engineering","volume":"4","year":"2015","journal-title":"Mol Ther Nucleic Acids"},{"key":"2026050501300524000_2026.04.27.721066v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3408"},{"key":"2026050501300524000_2026.04.27.721066v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-018-0148-2"},{"key":"2026050501300524000_2026.04.27.721066v1.20","doi-asserted-by":"crossref","unstructured":"Calligaris SD , Ricca M , Conget P. Cardiac stress test induced by dobutamine and monitored by cardiac catheterization in mice. J Vis Exp. 2013(72).","DOI":"10.3791\/50050"},{"issue":"12","key":"2026050501300524000_2026.04.27.721066v1.21","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1161\/CIRCRESAHA.123.323571","article-title":"Nitric Oxide Modulates Ca(2+) Leak and Arrhythmias via S-Nitrosylation of CaMKII","volume":"133","year":"2023","journal-title":"Circ Res"},{"key":"2026050501300524000_2026.04.27.721066v1.22","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.yjmcc.2022.12.002","article-title":"CaMKII and reactive oxygen species contribute to early reperfusion arrhythmias, but oxidation of CaMKIIdelta at methionines 281\/282 is not a determining factor","volume":"175","year":"2023","journal-title":"J Mol Cell Cardiol"},{"key":"2026050501300524000_2026.04.27.721066v1.23","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1387.033"},{"key":"2026050501300524000_2026.04.27.721066v1.24","doi-asserted-by":"crossref","unstructured":"Mesubi OO , Rokita AG , Abrol N , Wu Y , Chen B , Wang Q , et al. Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms. J Clin Invest. 2021;131(2).","DOI":"10.1172\/JCI95747"},{"key":"2026050501300524000_2026.04.27.721066v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2506"},{"issue":"9","key":"2026050501300524000_2026.04.27.721066v1.26","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.1172\/JCI133181","article-title":"MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII","volume":"130","year":"2020","journal-title":"J Clin Invest"},{"key":"2026050501300524000_2026.04.27.721066v1.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.216788"},{"key":"2026050501300524000_2026.04.27.721066v1.28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2010.01925.x"},{"key":"2026050501300524000_2026.04.27.721066v1.29","doi-asserted-by":"publisher","DOI":"10.2459\/01.JCM.0000223257.09062.17"},{"key":"2026050501300524000_2026.04.27.721066v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2008.01.068"},{"key":"2026050501300524000_2026.04.27.721066v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113982"},{"key":"2026050501300524000_2026.04.27.721066v1.32","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00021"},{"key":"2026050501300524000_2026.04.27.721066v1.33","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.240457"},{"key":"2026050501300524000_2026.04.27.721066v1.34","doi-asserted-by":"crossref","unstructured":"Huang F , Han X , Xiao X , Zhou J. Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development. Molecules. 2022;27(22).","DOI":"10.3390\/molecules27227728"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.27.721066","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T08:30:19Z","timestamp":1777969819000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.27.721066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,30]]},"references-count":34,"URL":"https:\/\/doi.org\/10.64898\/2026.04.27.721066","relation":{},"subject":[],"published":{"date-parts":[[2026,4,30]]},"subtype":"preprint"}}