<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">Tzimas, C.</style></author><author><style face="normal" font="default" size="100%">Terrovitis, J.</style></author><author><style face="normal" font="default" size="100%">Lehnart, S. E.</style></author><author><style face="normal" font="default" size="100%">Kranias, EG</style></author><author><style face="normal" font="default" size="100%">Sanoudou, D.</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition ameliorates arrhythmias elicited by junctin ablation under stress conditions</style></title><secondary-title><style face="normal" font="default" size="100%">Heart RhythmHeart RhythmHeart Rhythm</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Heart rhythm</style></alt-title><short-title><style face="normal" font="default" size="100%">Heart rhythmHeart rhythm</style></short-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">*Arrhythmias, Cardiac/metabolism/prevention &amp; control</style></keyword><keyword><style  face="normal" font="default" size="100%">Ablation Techniques</style></keyword><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">Benzylamines/*pharmacology</style></keyword><keyword><style  face="normal" font="default" size="100%">Calcium Signaling/*drug effects</style></keyword><keyword><style  face="normal" font="default" size="100%">Calcium-Binding Proteins/*metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Calcium/*metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Disease Models, Animal</style></keyword><keyword><style  face="normal" font="default" size="100%">Heart Failure/metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Mice</style></keyword><keyword><style  face="normal" font="default" size="100%">Models, Cardiovascular</style></keyword><keyword><style  face="normal" font="default" size="100%">Myocytes, Cardiac/drug effects/metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Phosphorylation/drug effects</style></keyword><keyword><style  face="normal" font="default" size="100%">Protein Kinase Inhibitors/pharmacology</style></keyword><keyword><style  face="normal" font="default" size="100%">Ryanodine Receptor Calcium Release Channel/metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Sarcoplasmic Reticulum/drug effects/metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Sulfonamides/*pharmacology</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2015</style></year><pub-dates><date><style  face="normal" font="default" size="100%">Jul</style></date></pub-dates></dates><number><style face="normal" font="default" size="100%">7</style></number><volume><style face="normal" font="default" size="100%">12</style></volume><pages><style face="normal" font="default" size="100%">1599-610</style></pages><isbn><style face="normal" font="default" size="100%">1556-3871 (Electronic)1547-5271 (Linking)</style></isbn><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">BACKGROUND: Aberrant calcium signaling is considered one of the key mechanisms contributing to arrhythmias, especially in the context of heart failure. In human heart failure, there is significant down-regulation of the sarcoplasmic reticulum (SR) protein junctin, and junctin deficiency in mice is associated with stress-induced arrhythmias. OBJECTIVE: The purpose of this study was to determine whether the increased SR Ca(2+) leak and arrhythmias associated with junctin ablation may be associated with increased calcium/calmodulin-dependent protein kinase II (CaMKII) activity and phosphorylation of the cardiac ryanodine receptor (RyR2) and whether pharmacologic inhibition of CaMKII activity may prevent these arrhythmias. METHODS: Using a combination of biochemical, cellular, and in vivo approaches, we tested the ability of KN-93 to reverse aberrant CaMKII phosphorylation of RyR2. Specifically, we performed protein phosphorylation analysis, in vitro cardiomyocyte contractility and Ca(2+) kinetics, and in vivo ECG analysis in junctin-deficient mice. RESULTS: In the absence of junctin, RyR2 channels displayed CaMKII-dependent hyperphosphorylation. Notably, CaMKII inhibition by KN-93 reduced the in vivo incidence of stress-induced ventricular tachycardia by 65% in junctin null mice. At the cardiomyocyte level, KN-93 reduced the percentage of junctin null cells exhibiting spontaneous Ca(2+) aftertransients and aftercontractions under stress conditions by 35% and 37%, respectively. At the molecular level, KN-93 blunted the CaMKII-mediated hyperphosphorylation of RyR2 and phospholamban under stress conditions. CONCLUSION: Our data suggest that CaMKII inhibition is effective in preventing arrhythmogenesis in the setting of junctin ablation through modulation of both SR Ca(2+) release and uptake. Thus, it merits further investigation as promising molecular therapy.</style></abstract><accession-num><style face="normal" font="default" size="100%">25814413</style></accession-num><notes><style face="normal" font="default" size="100%">Tzimas, ChristosTerrovitis, JohnLehnart, Stephan EKranias, Evangelia GSanoudou, DespinaengR01 HL026057/HL/NHLBI NIH HHS/R01 HL064018/HL/NHLBI NIH HHS/HL26057/HL/NHLBI NIH HHS/HL64018/HL/NHLBI NIH HHS/Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't2015/03/31 06:00Heart Rhythm. 2015 Jul;12(7):1599-610. doi: 10.1016/j.hrthm.2015.03.043. Epub 2015 Mar 23.</style></notes><custom2><style face="normal" font="default" size="100%">4485547</style></custom2><auth-address><style face="normal" font="default" size="100%">Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.3rd Department of Cardiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.Clinic of Cardiology &amp; Pulmonology, University Medical Center Goettingen, Goettingen, Germany.Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, Ohio.Molecular Biology Division, Biomedical Research Foundation of the Academy of Athens, Athens, Greece; Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. Electronic address: dsanoudou@med.uoa.gr.</style></auth-address></record></records></xml>