{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:40:44Z","timestamp":1790185244153,"version":"4.1.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","funder":[{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000222","name":"Heart and Stroke Foundation of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000222","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["Do 769\/4-1"],"award-info":[{"award-number":["Do 769\/4-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"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"}]},{"name":"Netherlands Organization for Scientific Research","award":["ZonMW Veni 91616057"],"award-info":[{"award-number":["ZonMW Veni 91616057"]}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2021,3,5]]},"abstract":"\n Rationale:<\/jats:title>\n \n The mechanisms underlying atrial fibrillation (AF), the most common clinical arrhythmia, are poorly understood. Nucleoplasmic Ca\n 2+<\/jats:sup>\n regulates gene expression, but the nature and significance of nuclear Ca\n 2+<\/jats:sup>\n -changes in AF are largely unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Objective:<\/jats:title>\n \n To elucidate mechanisms by which AF alters atrial-cardiomyocyte nuclear Ca\n 2+<\/jats:sup>\n ([Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n ) and CaMKII (Ca\n 2+<\/jats:sup>\n \/calmodulin-dependent protein kinase-II)-related signaling.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results:<\/jats:title>\n \n Atrial cardiomyocytes were isolated from control and AF dogs (kept in AF by atrial tachypacing [600 bpm \u00d7 1 week]). [Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n and cytosolic [Ca\n 2+<\/jats:sup>\n ] ([Ca\n 2+<\/jats:sup>\n ]\n Cyto<\/jats:sub>\n ) were recorded via confocal microscopy. Diastolic [Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n was greater than [Ca\n 2+<\/jats:sup>\n ]\n Cyto<\/jats:sub>\n under control conditions, while resting [Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n was similar to [Ca\n 2+<\/jats:sup>\n ]\n Cyto<\/jats:sub>\n ; both diastolic and resting [Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n increased with AF. IP\n 3<\/jats:sub>\n R (Inositol-trisphosphate receptor) stimulation produced larger [Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n increases in AF versus control cardiomyocytes, and IP\n 3<\/jats:sub>\n R-blockade suppressed the AF-related [Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n differences. AF upregulated nuclear protein expression of IP\n 3<\/jats:sub>\n R1 (IP\n 3<\/jats:sub>\n R-type 1) and of phosphorylated CaMKII (immunohistochemistry and immunoblot) while decreasing the nuclear\/cytosolic expression ratio for HDAC4 (histone deacetylase type-4). Isolated atrial cardiomyocytes tachypaced at 3 Hz for 24 hours mimicked AF-type [Ca\n 2+<\/jats:sup>\n ]\n Nuc<\/jats:sub>\n changes and L-type calcium current decreases versus 1-Hz-paced cardiomyocytes; these changes were prevented by IP\n 3<\/jats:sub>\n R knockdown with short-interfering RNA directed against IP\n 3<\/jats:sub>\n R1. Nuclear\/cytosolic HDAC4 expression ratio was decreased by 3-Hz pacing, while nuclear CaMKII phosphorylation was increased. Either CaMKII-inhibition (by autocamtide-2-related peptide) or IP\n 3<\/jats:sub>\n R-knockdown prevented the CaMKII-hyperphosphorylation and nuclear-to-cytosolic HDAC4 shift caused by 3-Hz pacing. In human atrial cardiomyocytes from AF patients, nuclear IP\n 3<\/jats:sub>\n R1-expression was significantly increased, with decreased nuclear\/nonnuclear HDAC4 ratio. MicroRNA-26a was predicted to target\n ITPR1<\/jats:italic>\n (confirmed by luciferase assay) and was downregulated in AF atrial cardiomyocytes; microRNA-26a silencing reproduced AF-induced IP\n 3<\/jats:sub>\n R1 upregulation and nuclear diastolic Ca\n 2+<\/jats:sup>\n -loading.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n AF increases atrial-cardiomyocyte nucleoplasmic [Ca\n 2+<\/jats:sup>\n ] by IP\n 3<\/jats:sub>\n R1-upregulation involving miR-26a, leading to enhanced IP\n 3<\/jats:sub>\n R1-CaMKII-HDAC4 signaling and L-type calcium current downregulation.\n <\/jats:p>\n <\/jats:sec>\n \n Graphic Abstract:<\/jats:title>\n \n A\n graphic abstract<\/jats:ext-link>\n is available for this article.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circresaha.120.317768","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T10:01:08Z","timestamp":1609322468000},"page":"619-635","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":35,"title":["Inositol Trisphosphate Receptors and Nuclear Calcium in Atrial Fibrillation"],"prefix":"10.1161","volume":"128","author":[{"given":"Xiao-Yan","family":"Qi","sequence":"first","affiliation":[{"name":"Medicine, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Canada (X.-Y.Q., F.V.H., J.X., F.X., L.R.V., D.D., S.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faezeh","family":"Vahdati Hassani","sequence":"additional","affiliation":[{"name":"Medicine, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Canada (X.-Y.Q., F.V.H., J.X., F.X., L.R.V., D.D., 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