Increased phosphorylation of Ca2+ 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, Hyelim Park, Boyoung Joung

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 Ca2+/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 Ca2+ handling proteins. These changes were partially reversed by an antiinflammatory treatment and CaMKII inhibition.

Original languageEnglish
Pages (from-to)2292-2301
Number of pages10
JournalCirculation Journal
Volume78
Issue number9
DOIs
Publication statusPublished - 2014 Sep 1

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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