{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T07:40:24Z","timestamp":1790322024684,"version":"4.1.0"},"reference-count":40,"publisher":"American Physiological Society","issue":"3","funder":[{"DOI":"10.13039\/100006108","name":"HHS | NIH | National Center for Advancing Translational Sciences (NCATS)","doi-asserted-by":"publisher","award":["UL1 TR000040"],"award-info":[{"award-number":["UL1 TR000040"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2015,8,1]]},"abstract":"<jats:p> Abnormal intracellular calcium (Ca<jats:sup>2+<\/jats:sup>) handling can trigger endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR) in an attempt to prevent cell death. Mechanical unloading with a left ventricular assist device (LVAD) relieves pressure-volume overload and promotes reverse remodeling of the failing myocardium. We hypothesized that mechanical unloading would alter the UPR in patients with advanced heart failure (HF). UPR was analyzed in paired myocardial tissue from 10 patients with dilated cardiomyopathy obtained during LVAD implantation and explantation. Samples from healthy hearts served as controls. Markers of UPR [binding immunoglobulin protein (BiP), phosphorylated (P-) eukaryotic initiation factor (eIF2\u03b1), and X-box binding protein (XBP1)] were significantly increased in HF, whereas LVAD support significantly decreased BiP, P-eIF2\u03b1, and XBP1s levels. Apoptosis as reflected by C\/EBP homologous protein and DNA damage were also significantly reduced after LVAD support. Improvement in left ventricular dimensions positively correlated with P-eIF2\u03b1\/eIF2\u03b1 and apoptosis level recovery. Furthermore, significant dysregulation of calcium-handling proteins [P-ryanodine receptor, Ca<jats:sup>2+<\/jats:sup> storing protein calsequestrin, Na<jats:sup>+<\/jats:sup>-Ca<jats:sup>2+<\/jats:sup> exchanger, sarcoendoplasmic reticulum Ca<jats:sup>2+<\/jats:sup>-ATPase (SERCA2a), ER chaperone protein calreticulin] was normalized after LVAD support. Reduced ER Ca<jats:sup>2+<\/jats:sup> content as a causative mechanism for UPR was confirmed using AC16 cells treated with a calcium ionophore (A23187) and SERCA2a inhibitor (thapsigargin). UPR activation and apoptosis are reduced after mechanical unloading, which may be mediated by the improvement of Ca<jats:sup>2+<\/jats:sup> handling in patients with advanced HF. These changes may impact the potential for myocardial recovery. <\/jats:p>","DOI":"10.1152\/ajpheart.00056.2015","type":"journal-article","created":{"date-parts":[[2015,6,9]],"date-time":"2015-06-09T08:10:59Z","timestamp":1433837459000},"page":"H459-H470","source":"Crossref","is-referenced-by-count":56,"title":["Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy"],"prefix":"10.1152","volume":"309","author":[{"given":"Estibaliz","family":"Castillero","sequence":"first","affiliation":[{"name":"Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Akashi","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Pendrak","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halit","family":"Yerebakan","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Najjar","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshifumi","family":"Naka","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Mancini","sequence":"additional","affiliation":[{"name":"Division of Cardiology, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Lee","family":"Sweeney","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanine","family":"D\u2032Armiento","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziad A.","family":"Ali","sequence":"additional","affiliation":[{"name":"Division of Cardiology, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Christian","family":"Schulze","sequence":"additional","affiliation":[{"name":"Division of Cardiology, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"George","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, New York Presbyterian Hospital - College of Physicians and Surgeons of Columbia University, New York, New York;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.72.2.463"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.06.008"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2174\/157340308785160606"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004954"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301413"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.03.003"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.97.23.2316"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1992.262.5.H1387"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.040261"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.5.992"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-4975(96)00437-7"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr106"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2007.10.017"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.5.641"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.22.2713"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2131\/jts.31.149"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2091-2-4"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.81.6.1083"},{"key":"B19","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3724\/SP.J.1263.2012.02292","volume":"9","author":"Liu CL","year":"2012","journal-title":"J Geriatr Cardiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1782"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.22.2383"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.412783"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-891-7"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/11.suppl_C.8"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(00)00703-8"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(95)00176-X"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2199"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.16.2105"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.113.004796"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(01)00470-9"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.75.3.443"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2012.11.011"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000129233.51320.92"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000233317.70421.03"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2010.08.005"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.184978"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcin.2012.12.122"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.06.030"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2001.280.4.C843"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.302421"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00056.2015","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,8]],"date-time":"2019-09-08T18:37:06Z","timestamp":1567967826000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00056.2015"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,1]]},"references-count":40,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2015,8,1]]}},"alternative-id":["10.1152\/ajpheart.00056.2015"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00056.2015","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,1]]}}}