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In contrast, the role played by SR Ca2+ uptake under these stress conditions remains controversial. We tested the hypothesis that an increase in SR Ca2+ uptake is able to attenuate reperfusion arrhythmias and cardiac injury elicited by increased RyR2-Ser2814 phosphorylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We used WT mice, which have been previously shown to exhibit a transient increase in RyR2-Ser2814 phosphorylation at the onset of reperfusion; mice with constitutive pseudo-phosphorylation of RyR2 at Ser2814 (S2814D) to exacerbate CaMKII-dependent reperfusion arrhythmias and cardiac damage, and phospholamban (PLN)-deficient-S2814D knock-in (SDKO) mice resulting from crossbreeding S2814D with phospholamban knockout deficient (PLNKO) mice. At baseline, S2814D and SDKO mice had structurally normal hearts. Moreover none of the strains were arrhythmic before ischaemia. Upon cardiac I\/R, WT, and S2814D hearts exhibited abundant arrhythmias that were prevented by PLN ablation. In contrast, PLN ablation increased infarct size compared with WT and S2814D hearts. Mechanistically, the enhanced SR Ca2+ sequestration evoked by PLN ablation in SDKO hearts prevented arrhythmogenic events upon reperfusion by fragmenting SR Ca2+ waves into non-propagated and non-arrhythmogenic events (mini-waves). Conversely, the increase in SR Ca2+ sequestration did not reduce but rather exacerbated I\/R-induced SR Ca2+ leak, as well as mitochondrial alterations, which were greatly avoided by inhibition of RyR2. These results indicate that the increase in SR Ca2+ uptake is ineffective in preventing the enhanced SR Ca2+ leak of PLN ablated myocytes from either entering into nearby mitochondria and\/or activating additional CaMKII pathways, contributing to cardiac damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results demonstrate that increasing SR Ca2+ uptake by PLN ablation can prevent the arrhythmic events triggered by CaMKII-dependent phosphorylation of RyR2-induced SR Ca2+ leak. These findings underscore the benefits of increasing SERCA2a activity in the face of SR Ca2+ triggered arrhythmias. However, enhanced SERCA2a cannot prevent but rather exacerbates I\/R cardiac injury.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvy213","type":"journal-article","created":{"date-parts":[[2018,8,27]],"date-time":"2018-08-27T20:19:03Z","timestamp":1535401143000},"page":"556-569","source":"Crossref","is-referenced-by-count":36,"title":["Ablation of phospholamban rescues reperfusion arrhythmias but exacerbates myocardium infarction in hearts with Ca2+\/calmodulin kinase II constitutive phosphorylation of ryanodine receptors"],"prefix":"10.1093","volume":"115","author":[{"given":"Carlos A","family":"Valverde","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriela","family":"Mazzocchi","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariano N","family":"Di Carlo","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandro","family":"Ciocci Pardo","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nehuen","family":"Salas","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Ines","family":"Ragone","sequence":"additional","affiliation":[{"name":"Grupo de Farmacolog\u00eda Experimental, (GFEYEC), Departamento of Ciencias Biol\u00f3gicas, Facultad de Ciencias Exactas \u2013 CONICET., La Plata, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan I","family":"Felice","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alejandra","family":"Cely-Ortiz","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia E","family":"Consolini","sequence":"additional","affiliation":[{"name":"Grupo de Farmacolog\u00eda Experimental, (GFEYEC), Departamento of Ciencias Biol\u00f3gicas, Facultad de Ciencias Exactas \u2013 CONICET., La Plata, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Portiansky","sequence":"additional","affiliation":[{"name":"Laboratorio de An\u00e1lisis de Im\u00e1genes, Facultad de Cs. Veterinarias, UNLP, La Plata, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Mosca","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. Cingolani\u2019, CCT-La Plata-CONICET, Facultad de Cs. M\u00e9dicas, UNLP, 60 y 120 s\/n, La Plata CP, Argentina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelia G","family":"Kranias","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xander H T","family":"Wehrens","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, Center for Space Medicine, Baylor College of Medicine, Houston, TX, USA"},{"name":"Department of Medicine (in Cardiology), Cardiovascular Research Institute, Center for Space Medicine, Baylor College of Medicine, Houston, TX, USA"},{"name":"Department of Pediatrics, Cardiovascular Research Institute, Center for Space Medicine, Baylor College of Medicine, Houston, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"Mattiazzi","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Cardiovasculares \u2018Dr. Horacio E. 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