<?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%">Haghighi, K.</style></author><author><style face="normal" font="default" size="100%">Pritchard, T. J.</style></author><author><style face="normal" font="default" size="100%">Liu, G. S.</style></author><author><style face="normal" font="default" size="100%">Singh, V. P.</style></author><author><style face="normal" font="default" size="100%">Bidwell, P.</style></author><author><style face="normal" font="default" size="100%">Lam, C. K.</style></author><author><style face="normal" font="default" size="100%">Vafiadaki, E.</style></author><author><style face="normal" font="default" size="100%">Das, P</style></author><author><style face="normal" font="default" size="100%">Ma, J.</style></author><author><style face="normal" font="default" size="100%">Kunduri, S.</style></author><author><style face="normal" font="default" size="100%">Sanoudou, D.</style></author><author><style face="normal" font="default" size="100%">Florea, S.</style></author><author><style face="normal" font="default" size="100%">Vanderbilt, E.</style></author><author><style face="normal" font="default" size="100%">Wang, H. S.</style></author><author><style face="normal" font="default" size="100%">Rubinstein, J.</style></author><author><style face="normal" font="default" size="100%">Hajjar, R. J.</style></author><author><style face="normal" font="default" size="100%">Kranias, EG</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias</style></title><secondary-title><style face="normal" font="default" size="100%">J Mol Cell CardiolJ Mol Cell CardiolJ Mol Cell Cardiol</style></secondary-title><alt-title><style face="normal" font="default" size="100%">Journal of molecular and cellular cardiology</style></alt-title><short-title><style face="normal" font="default" size="100%">Journal of molecular and cellular cardiologyJournal of molecular and cellular cardiology</style></short-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Animals</style></keyword><keyword><style  face="normal" font="default" size="100%">Arrhythmias, Cardiac/*genetics/*physiopathology</style></keyword><keyword><style  face="normal" font="default" size="100%">Calcium Signaling/genetics</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%">Catecholamines/pharmacology</style></keyword><keyword><style  face="normal" font="default" size="100%">Diastole/drug effects</style></keyword><keyword><style  face="normal" font="default" size="100%">Heart/drug effects/physiopathology</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Isoproterenol/pharmacology</style></keyword><keyword><style  face="normal" font="default" size="100%">Kinetics</style></keyword><keyword><style  face="normal" font="default" size="100%">Mice, Transgenic</style></keyword><keyword><style  face="normal" font="default" size="100%">Myocardial Contraction/drug effects</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%">Polymorphism, Single Nucleotide/*genetics</style></keyword><keyword><style  face="normal" font="default" size="100%">Proteins/*genetics/metabolism</style></keyword><keyword><style  face="normal" font="default" size="100%">Rats</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%">Sodium-Calcium Exchanger/metabolism</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%">Dec</style></date></pub-dates></dates><number><style face="normal" font="default" size="100%">Pt B</style></number><volume><style face="normal" font="default" size="100%">89</style></volume><pages><style face="normal" font="default" size="100%">349-59</style></pages><isbn><style face="normal" font="default" size="100%">1095-8584 (Electronic)0022-2828 (Linking)</style></isbn><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">A hallmark of human and experimental heart failure is deficient sarcoplasmic reticulum (SR) Ca-uptake reflecting impaired contractile function. This is at least partially attributed to dephosphorylation of phospholamban by increased protein phosphatase 1 (PP1) activity. Indeed inhibition of PP1 by transgenic overexpression or gene-transfer of constitutively active inhibitor-1 improved Ca-cycling, preserved function and decreased fibrosis in small and large animal models of heart failure, suggesting that inhibitor-1 may represent a potential therapeutic target. We recently identified a novel human polymorphism (G109E) in the inhibitor-1 gene with a frequency of 7% in either normal or heart failure patients. Transgenic mice, harboring cardiac-specific expression of G109E inhibitor-1, exhibited decreases in contractility, Ca-kinetics and SR Ca-load. These depressive effects were relieved by isoproterenol stimulation. Furthermore, stress conditions (2Hz +/- Iso) induced increases in Ca-sparks, Ca-waves (60% of G109E versus 20% in wild types) and after-contractions (76% of G109E versus 23% of wild types) in mutant cardiomyocytes. Similar findings were obtained by acute expression of the G109E variant in adult cardiomyocytes in the absence or presence of endogenous inhibitor-1. The underlying mechanisms included reduced binding of mutant inhibitor-1 to PP1, increased PP1 activity, and dephosphorylation of phospholamban at Ser16 and Thr17. However, phosphorylation of the ryanodine receptor at Ser2808 was not altered while phosphorylation at Ser2814 was increased, consistent with increased activation of Ca/calmodulin-dependent protein kinase II (CaMKII), promoting aberrant SR Ca-release. Parallel in vivo studies revealed that mutant mice developed ventricular ectopy and complex ventricular arrhythmias (including bigeminy, trigeminy and ventricular tachycardia), when challenged with isoproterenol. Inhibition of CaMKII activity by KN-93 prevented the increased propensity to arrhythmias. These findings suggest that the human G109E inhibitor-1 variant impairs SR Ca-cycling and promotes arrhythmogenesis under stress conditions, which may present an additional insult in the compromised function of heart failure carriers.</style></abstract><accession-num><style face="normal" font="default" size="100%">26455482</style></accession-num><notes><style face="normal" font="default" size="100%">Haghighi, KobraPritchard, Tracy JLiu, Guan-ShengSingh, Vivek PBidwell, PhilipLam, Chi KeungVafiadaki, ElizabethDas, ParthibMa, JianyongKunduri, SwatiSanoudou, DespinaFlorea, StelaVanderbilt, EricaWang, Hong-ShangRubinstein, JackHajjar, Roger JKranias, Evangelia GengHL093183/HL/NHLBI NIH HHS/HL026057/HL/NHLBI NIH HHS/R01 HL026057/HL/NHLBI NIH HHS/T32 HL125204/HL/NHLBI NIH HHS/HL064018/HL/NHLBI NIH HHS/R01 HL064018/HL/NHLBI NIH HHS/Research Support, N.I.H., ExtramuralEngland2015/10/13 06:00J Mol Cell Cardiol. 2015 Dec;89(Pt B):349-59. doi: 10.1016/j.yjmcc.2015.10.004. Epub 2015 Oct 9.</style></notes><custom2><style face="normal" font="default" size="100%">4689614</style></custom2><auth-address><style face="normal" font="default" size="100%">Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, United States.Molecular Biology Division, Biomedical Research Foundation, Academy of Athens, Greece.Molecular Biology Division, Biomedical Research Foundation, Academy of Athens, Greece; 4th Department of Internal Medicine, Medical School, University of Athens and Attikon Hospital, Greece.Division of Cardiology, Internal Medicine, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, United States.Cardiovascular Research Center, Ichan School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029, United States.Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, United States; Molecular Biology Division, Biomedical Research Foundation, Academy of Athens, Greece. Electronic address: litsa.kranias@uc.edu.</style></auth-address></record></records></xml>