PMID- 25814413
OWN - NLM
STAT- MEDLINE
DCOM- 20160427
LR  - 20240213
IS  - 1556-3871 (Electronic)
IS  - 1547-5271 (Print)
IS  - 1547-5271 (Linking)
VI  - 12
IP  - 7
DP  - 2015 Jul
TI  - Calcium/calmodulin-dependent protein kinase II (CaMKII) inhibition ameliorates 
      arrhythmias elicited by junctin ablation under stress conditions.
PG  - 1599-610
LID - S1547-5271(15)00342-2 [pii]
LID - 10.1016/j.hrthm.2015.03.043 [doi]
AB  - 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.
CI  - Copyright (c) 2015. Published by Elsevier Inc.
FAU - Tzimas, Christos
AU  - Tzimas C
AD  - Molecular Biology Division, Biomedical Research Foundation of the Academy of 
      Athens, Athens, Greece.
FAU - Terrovitis, John
AU  - Terrovitis J
AD  - 3rd Department of Cardiology, Medical School, National and Kapodistrian 
      University of Athens, Athens, Greece.
FAU - Lehnart, Stephan E
AU  - Lehnart SE
AD  - Clinic of Cardiology & Pulmonology, University Medical Center Goettingen, 
      Goettingen, Germany.
FAU - Kranias, Evangelia G
AU  - Kranias EG
AD  - 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.
FAU - Sanoudou, Despina
AU  - Sanoudou D
AD  - 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.
LA  - eng
GR  - R01 HL026057/HL/NHLBI NIH HHS/United States
GR  - HL64018/HL/NHLBI NIH HHS/United States
GR  - R01 HL064018/HL/NHLBI NIH HHS/United States
GR  - HL26057/HL/NHLBI NIH HHS/United States
GR  - R37 HL026057/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150323
PL  - United States
TA  - Heart Rhythm
JT  - Heart rhythm
JID - 101200317
RN  - 0 (Benzylamines)
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Ryanodine Receptor Calcium Release Channel)
RN  - 0 (Sulfonamides)
RN  - 0 (phospholamban)
RN  - 139298-40-1 (KN 93)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Ablation Techniques
MH  - Animals
MH  - *Arrhythmias, Cardiac/metabolism/prevention & control
MH  - Benzylamines/*pharmacology
MH  - Calcium/*metabolism
MH  - Calcium Signaling/*drug effects
MH  - Calcium-Binding Proteins/*metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism
MH  - Disease Models, Animal
MH  - Heart Failure/metabolism
MH  - Mice
MH  - Models, Cardiovascular
MH  - Myocytes, Cardiac/drug effects/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Ryanodine Receptor Calcium Release Channel/metabolism
MH  - Sarcoplasmic Reticulum/drug effects/metabolism
MH  - Sulfonamides/*pharmacology
PMC - PMC4485547
MID - NIHMS684218
OTO - NOTNLM
OT  - Arrhythmia
OT  - Calcium/calmodulin-dependent protein kinase II
OT  - Isoproterenol
OT  - Junctin
OT  - Ryanodine receptor
COIS- Conflict of interests: None
EDAT- 2015/03/31 06:00
MHDA- 2016/04/28 06:00
PMCR- 2016/07/01
CRDT- 2015/03/28 06:00
PHST- 2014/07/08 00:00 [received]
PHST- 2015/03/28 06:00 [entrez]
PHST- 2015/03/31 06:00 [pubmed]
PHST- 2016/04/28 06:00 [medline]
PHST- 2016/07/01 00:00 [pmc-release]
AID - S1547-5271(15)00342-2 [pii]
AID - 10.1016/j.hrthm.2015.03.043 [doi]
PST - ppublish
SO  - Heart Rhythm. 2015 Jul;12(7):1599-610. doi: 10.1016/j.hrthm.2015.03.043. Epub 
      2015 Mar 23.