{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T01:22:48Z","timestamp":1747185768712,"version":"3.40.5"},"reference-count":47,"publisher":"Wiley","issue":"15","license":[{"start":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T00:00:00Z","timestamp":1592870400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Hartstichting","doi-asserted-by":"publisher","award":["CVON\u2010PREDICT 2012\u201010","CVON\u2010PREDICT 2018\u201030"],"award-info":[{"award-number":["CVON\u2010PREDICT 2012\u201010","CVON\u2010PREDICT 2018\u201030"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the diseased and remodelled heart, increased activity and expression of Ca<jats:sup>2+\/<\/jats:sup>calmodulin\u2010dependent protein kinase II (CaMKII), an excess of fibrosis, and a decreased electrical coupling and cellular excitability leads to disturbed calcium homeostasis and tissue integrity. This subsequently leads to increased arrhythmia vulnerability and contractile dysfunction. Here, we investigated the combination of CaMKII inhibition (using genetically modified mice expressing the autocamtide\u20103\u2010related\u2010peptide (AC3I)) together with eplerenone treatment (AC3I\u2010Epler) to prevent electrophysiological remodelling, fibrosis and subsequent functional deterioration in a mouse model of chronic pressure overload. We compared AC3I\u2010Epler mice with mice only subjected to mineralocorticoid receptor (MR) antagonism (WT\u2010Epler) and mice with only CaMKII inhibition (AC3I\u2010No). Our data show that a combined CaMKII inhibition together with MR antagonism mitigates contractile deterioration as was manifested by a preservation of ejection fraction, fractional shortening, global longitudinal strain, peak strain and contractile synchronicity. Furthermore, patchy fibrosis formation was reduced, potentially via inhibition of pro\u2010fibrotic TGF\u2010\u03b2\/SMAD3 signalling, which related to a better global contractile performance and a slightly depressed incidence of arrhythmias. Furthermore, the level of patchy fibrosis appeared significantly correlated to eplerenone dose. The addition of eplerenone to CaMKII inhibition potentiates the effects of CaMKII inhibition on pro\u2010fibrotic pathways. As a result of the applied strategy, limiting patchy fibrosis adheres to a higher synchronicity of contraction and an overall better contractile performance which fits with a tempered arrhythmogenesis.<\/jats:p>","DOI":"10.1111\/jcmm.15355","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T16:17:48Z","timestamp":1592929068000},"page":"8417-8429","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A combined CaMKII inhibition and mineralocorticoid receptor antagonism via eplerenone inhibits functional deterioration in chronic pressure overloaded mice"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6651-4528","authenticated-orcid":false,"given":"Helen E.","family":"Driessen","sequence":"first","affiliation":[{"name":"Division of Heart &amp; Lungs Department of Medical Physiology University Medical Centre Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magda S.","family":"Fontes","sequence":"additional","affiliation":[{"name":"Division of Heart &amp; Lungs Department of Medical Physiology University Medical Centre Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonie","family":"van Stuijvenberg","sequence":"additional","affiliation":[{"name":"Division of Heart &amp; Lungs Department of Medical Physiology University Medical Centre Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maike A.","family":"Brans","sequence":"additional","affiliation":[{"name":"Division of Heart &amp; Lungs Department of Medical Physiology University Medical Centre Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie\u2010Jose","family":"Goumans","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology LUMC Leiden The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc A.","family":"Vos","sequence":"additional","affiliation":[{"name":"Division of Heart &amp; Lungs Department of Medical Physiology University Medical Centre Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toon A.","family":"van Veen","sequence":"additional","affiliation":[{"name":"Division of Heart &amp; Lungs Department of Medical Physiology University Medical Centre Utrecht Utrecht The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,6,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.43.28424"},{"key":"e_1_2_9_3_1","first-page":"H982","article-title":"Ca\u2010dependent facilitation of cardiac Ca current is due to Ca\u2010calmodulin\u2010dependent protein kinase","volume":"267","author":"Yuan W","year":"1994","journal-title":"Am 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