{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:26:00Z","timestamp":1790195160718,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["V 530"],"award-info":[{"award-number":["V 530"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["I3301-B31"],"award-info":[{"award-number":["I3301-B31"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"BioTechMed-Graz","award":["YRG Senka Holzer"],"award-info":[{"award-number":["YRG Senka Holzer"]}]},{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K99HL138160"],"award-info":[{"award-number":["K99HL138160"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL142282"],"award-info":[{"award-number":["R01-HL142282"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["P01-HL141084"],"award-info":[{"award-number":["P01-HL141084"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R37-HL028413"],"award-info":[{"award-number":["R37-HL028413"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL145459"],"award-info":[{"award-number":["R01-HL145459"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,10,9]]},"abstract":"<jats:sec>\n            <jats:title>Rationale:<\/jats:title>\n            <jats:p>\n              CaMKII (Ca\n              <jats:sup>2+<\/jats:sup>\n              -Calmodulin dependent protein kinase) \u03b4C activation is implicated in pathological progression of heart failure (HF) and CaMKII\u03b4C transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca\n              <jats:sup>2+<\/jats:sup>\n              handling and CaMKII activation in hypertrophy and HF.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Objective:<\/jats:title>\n            <jats:p>To measure time- and location-dependent activation of CaMKII\u03b4C signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKII\u03b4C transgenic mice.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results:<\/jats:title>\n            <jats:p>\n              We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKII\u03b4-knockout), CaMKII\u03b4C transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKII\u03b4C activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKII\u03b4 activation caused a compensatory increase in sarcoplasmic reticulum Ca\n              <jats:sup>2+<\/jats:sup>\n              content, Ca\n              <jats:sup>2+<\/jats:sup>\n              transient amplitude, and [Ca\n              <jats:sup>2+<\/jats:sup>\n              ] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKII\u03b4 TG mice (6\u20138 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11\u201313 weeks, respectively), during which time the compensatory Ca\n              <jats:sup>2+<\/jats:sup>\n              transient effects reversed, but further increases in nuclear and time-averaged [Ca\n              <jats:sup>2+<\/jats:sup>\n              ] and CaMKII activation occurred. CaMKII\u03b4 TG mice lacking \u03b4B exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKII\u03b4 expression, especially for CaMKII\u03b4C in nuclear fractions.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              We conclude that in early TAC perinuclear CaMKII\u03b4C activation promotes adaptive increases in myocyte Ca\n              <jats:sup>2+<\/jats:sup>\n              transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca\n              <jats:sup>2+<\/jats:sup>\n              -CaMKII\u03b4C axis contributes to eccentric hypertrophy and HF.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.120.316947","type":"journal-article","created":{"date-parts":[[2020,8,21]],"date-time":"2020-08-21T14:34:53Z","timestamp":1598020493000},"page":"1159-1178","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":59,"title":["CaMKII\u03b4C Drives Early Adaptive Ca\n            <sup>2+<\/sup>\n            Change and Late Eccentric Cardiac Hypertrophy"],"prefix":"10.1161","volume":"127","author":[{"given":"Senka","family":"Ljubojevic-Holzer","sequence":"first","affiliation":[{"name":"Department of Cardiology (S.L.-H., N.D., J.V., M.A., I.M., M.S., S.R., M.W., D.v.L., S. Sedej), Medical University of Graz, Austria."},{"name":"Department of Pharmacology, University of California, Davis, CA (S.L.-H., A.W.H., S.M., B.M.W., J.B., D.M.B.)."},{"name":"BioTechMed Graz, Austria (S.L.-H., J.V., S. Sedej)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony W.","family":"Herren","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, CA (S.L.-H., A.W.H., S.M., B.M.W., J.B., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"Djalinac","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.L.-H., N.D., J.V., M.A., I.M., M.S., S.R., M.W., D.v.L., S. Sedej), Medical University of Graz, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0102-7902","authenticated-orcid":true,"given":"Julia","family":"Voglhuber","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.L.-H., N.D., J.V., M.A., I.M., M.S., S.R., M.W., D.v.L., S. Sedej), Medical University of Graz, Austria."},{"name":"BioTechMed Graz, Austria (S.L.-H., J.V., S. Sedej)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Morotti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, CA (S.L.-H., A.W.H., S.M., B.M.W., J.B., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Holzer","sequence":"additional","affiliation":[{"name":"Otto-Loewi Research Centre, Division of Pharmacology (M.H.), Medical University of Graz, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent M.","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California, Davis, CA (S.L.-H., A.W.H., S.M., B.M.W., J.B., D.M.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Abdellatif","sequence":"additional","affiliation":[{"name":"Department of Cardiology (S.L.-H., N.D., J.V., M.A., I.M., M.S., S.R., M.W., D.v.L., S. 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