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

18 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

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Myocarditis
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Phosphorylation
Proteins
Cardiac Myosins
Action Potentials
Cardiac Arrhythmias
Fibrosis
Swine
Steroids
High Mobility Group Proteins
Ryanodine Receptor Calcium Release Channel
Injections
Protein Kinase Inhibitors
Ventricular Tachycardia
Prednisolone
Cyclic AMP-Dependent Protein Kinases
Immunoblotting
Cause of Death
Interleukin-6

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Park, H., Park, H., Lee, D., Oh, S., Lim, J., Hwang, H. J., ... Joung, B. (2014). Increased phosphorylation of Ca2+ handling proteins as a proarrhythmic mechanism in myocarditis. Circulation Journal, 78(9), 2292-2301. https://doi.org/10.1253/circj.CJ-14-0277
Park, Hyelim ; Park, Hyewon ; Lee, Dajeong ; Oh, Sujung ; Lim, Jisoo ; Hwang, Hye Jin ; Park, Sungha ; Pak, Hui Nam ; Lee, Moon Hyoung ; Joung, Boyoung ; Park, Hyelim ; Joung, Boyoung. / Increased phosphorylation of Ca2+ handling proteins as a proarrhythmic mechanism in myocarditis. In: Circulation Journal. 2014 ; Vol. 78, No. 9. pp. 2292-2301.
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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.",
author = "Hyelim Park and Hyewon Park and Dajeong Lee and Sujung Oh and Jisoo Lim and Hwang, {Hye Jin} and Sungha Park and Pak, {Hui Nam} and Lee, {Moon Hyoung} and Boyoung Joung and Hyelim Park and Boyoung Joung",
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Park, H, Park, H, Lee, D, Oh, S, Lim, J, Hwang, HJ, Park, S, Pak, HN, Lee, MH, Joung, B, Park, H & Joung, B 2014, 'Increased phosphorylation of Ca2+ handling proteins as a proarrhythmic mechanism in myocarditis', Circulation Journal, vol. 78, no. 9, pp. 2292-2301. https://doi.org/10.1253/circj.CJ-14-0277

Increased phosphorylation of Ca2+ handling proteins as a proarrhythmic mechanism in myocarditis. / Park, Hyelim; Park, Hyewon; Lee, Dajeong; Oh, Sujung; Lim, Jisoo; Hwang, Hye Jin; Park, Sungha; Pak, Hui Nam; Lee, Moon Hyoung; Joung, Boyoung; Park, Hyelim; Joung, Boyoung.

In: Circulation Journal, Vol. 78, No. 9, 01.09.2014, p. 2292-2301.

Research output: Contribution to journalArticle

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T1 - Increased phosphorylation of Ca2+ handling proteins as a proarrhythmic mechanism in myocarditis

AU - Park, Hyelim

AU - Park, Hyewon

AU - Lee, Dajeong

AU - Oh, Sujung

AU - Lim, Jisoo

AU - Hwang, Hye Jin

AU - Park, Sungha

AU - Pak, Hui Nam

AU - Lee, Moon Hyoung

AU - Joung, Boyoung

AU - Park, Hyelim

AU - Joung, Boyoung

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

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