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Increased phosphorylation of ca(2+) handling proteins as a proarrhythmic mechanism in myocarditis.

 Hyelim Park  ;  Hyewon Park  ;  Dajeong Lee  ;  Sujung Oh  ;  Jisoo Lim  ;  Hye jin Hwang  ;  Sungha Park  ;  Hui-Nam Pak  ;  Moon-Hyoung Lee  ;  Boyoung Joung 
 Circulation Journal, Vol.78(9) : 2292-2301, 2014 
Journal Title
 Circulation Journal 
Issue Date
Action Potentials/drug effects ; Animals ; Anti-Inflammatory Agents/administration & dosage ; Anti-Inflammatory Agents/adverse effects ; Arrhythmias, Cardiac/chemically induced ; Arrhythmias, Cardiac/metabolism ; Arrhythmias, Cardiac/pathology ; Arrhythmias, Cardiac/physiopathology ; Calcium/metabolism* ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; Cyclic AMP-Dependent Protein Kinases/metabolism* ; Male ; Myocarditis*/chemically induced ; Myocarditis*/metabolism ; Myocarditis*/pathology ; Myocarditis*/physiopathology ; Myosins/toxicity ; Phosphorylation/drug effects ; Prednisolone/adverse effects ; Prednisolone/pharmacology ; Rats ; Rats, Inbred Lew
Arrhythmia ; Ca2+/calmodulin-dependent protein kinase II ; Inflammation ; Myocarditis
BACKGROUND: Because fatal arrhythmia is an important cause of death in patients with myocarditis, we investigated the proarrhythmic mechanisms of experimental autoimmune myocarditis. METHODS AND RESULTS: Myocarditis was induced by injection of 2 mg porcine cardiac myosin into the footpads of adult Lewis rats on days 1 and 8 (Myo, n=15) and the results compared with Control rats (Control, n=15). In an additional 15 rats, 6 mg/kg prednisolone was injected into the gluteus muscle before the injection of porcine cardiac myosin on days 1 and 8 (MyoS, n=15). Hearts with myocarditis had longer action potential duration (APD), slower conduction velocity (CV; P<0.01 vs. Control), higher CV heterogeneity, greater fibrosis, higher levels of immunoblotting of high-mobility group protein B1, interleukin 6 and tumor necrosis factor-α proteins. Steroid treatment partially reversed the translations for myocarditis, CV heterogeneity, reduced APD at 90% recovery to baseline, increased CV (P<0.01), and reversed fibrosis (P<0.05). Programmed stimulation triggered sustained ventricular tachycardia in Myo rats (n=4/5), but not in controls (n=0/5) or Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor (KN93) treated Myo rats (n=0/5, P=0.01). CaMKII autophosphorylation at Thr287 (201%), and RyR2 phosphorylation at Ser2808 (protein kinase A/CaMKII site, 126%) and Ser2814 (CaMKII site, 21%) were increased in rats with myocarditis and reversed by steroid. CONCLUSIONS: The myocarditis group had an increased incidence of arrhythmia caused by increased phosphorylation of Ca(2+)handling proteins. These changes were partially reversed by an antiinflammatory treatment and CaMKII inhibition.
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1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Sung Ha(박성하) ORCID logo https://orcid.org/0000-0001-5362-478X
Park, Hye Lim(박혜림)
Pak, Hui Nam(박희남) ORCID logo https://orcid.org/0000-0002-3256-3620
Lee, Da Jeong(이다정)
Lee, Moon Hyoung(이문형) ORCID logo https://orcid.org/0000-0002-7268-0741
Joung, Bo Young(정보영) ORCID logo https://orcid.org/0000-0001-9036-7225
Hwang, Hye Jin(황혜진)
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