Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure

Ralph J. Van Oort, Mark D. McCauley, Sayali S. Dixit, Laetitia Pereira, Yi Yang, Jonathan L. Respress, Qiongling Wang, Angela C. De Almeida, Darlene G. Skapura, Mark E. Anderson, Donald M Bers, Xander H T Wehrens

Research output: Contribution to journalArticle

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Abstract

Background- Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. Methods and results- Mice in which the S2814 Ca/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca release events, resulting in reduced sarcoplasmic reticulum Ca load on confocal microscopy. These Ca release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery. Conclusions- Our results suggest that Ca/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.

Original languageEnglish (US)
Pages (from-to)2669-2679
Number of pages11
JournalCirculation
Volume122
Issue number25
DOIs
StatePublished - Dec 21 2010

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Ryanodine Receptor Calcium Release Channel
Cardiac Arrhythmias
Heart Failure
Phosphorylation
Sarcoplasmic Reticulum
Sudden Cardiac Death
Constriction
Lipid Bilayers
Ventricular Tachycardia
Sudden Death
Caffeine
Confocal Microscopy
Electric Stimulation
Epinephrine

Keywords

  • arrhythmia
  • calcium
  • calcium-calmodulin-dependent protein kinase type 2
  • heart failure
  • ryanodine receptor calcium release channel
  • sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. / Van Oort, Ralph J.; McCauley, Mark D.; Dixit, Sayali S.; Pereira, Laetitia; Yang, Yi; Respress, Jonathan L.; Wang, Qiongling; De Almeida, Angela C.; Skapura, Darlene G.; Anderson, Mark E.; Bers, Donald M; Wehrens, Xander H T.

In: Circulation, Vol. 122, No. 25, 21.12.2010, p. 2669-2679.

Research output: Contribution to journalArticle

Van Oort, RJ, McCauley, MD, Dixit, SS, Pereira, L, Yang, Y, Respress, JL, Wang, Q, De Almeida, AC, Skapura, DG, Anderson, ME, Bers, DM & Wehrens, XHT 2010, 'Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure', Circulation, vol. 122, no. 25, pp. 2669-2679. https://doi.org/10.1161/CIRCULATIONAHA.110.982298
Van Oort, Ralph J. ; McCauley, Mark D. ; Dixit, Sayali S. ; Pereira, Laetitia ; Yang, Yi ; Respress, Jonathan L. ; Wang, Qiongling ; De Almeida, Angela C. ; Skapura, Darlene G. ; Anderson, Mark E. ; Bers, Donald M ; Wehrens, Xander H T. / Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. In: Circulation. 2010 ; Vol. 122, No. 25. pp. 2669-2679.
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abstract = "Background- Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. Methods and results- Mice in which the S2814 Ca/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca release events, resulting in reduced sarcoplasmic reticulum Ca load on confocal microscopy. These Ca release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery. Conclusions- Our results suggest that Ca/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.",
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T1 - Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure

AU - Van Oort, Ralph J.

AU - McCauley, Mark D.

AU - Dixit, Sayali S.

AU - Pereira, Laetitia

AU - Yang, Yi

AU - Respress, Jonathan L.

AU - Wang, Qiongling

AU - De Almeida, Angela C.

AU - Skapura, Darlene G.

AU - Anderson, Mark E.

AU - Bers, Donald M

AU - Wehrens, Xander H T

PY - 2010/12/21

Y1 - 2010/12/21

N2 - Background- Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. Methods and results- Mice in which the S2814 Ca/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca release events, resulting in reduced sarcoplasmic reticulum Ca load on confocal microscopy. These Ca release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery. Conclusions- Our results suggest that Ca/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.

AB - Background- Approximately half of patients with heart failure die suddenly as a result of ventricular arrhythmias. Although abnormal Ca release from the sarcoplasmic reticulum through ryanodine receptors (RyR2) has been linked to arrhythmogenesis, the molecular mechanisms triggering release of arrhythmogenic Ca remain unknown. We tested the hypothesis that increased RyR2 phosphorylation by Ca/calmodulin-dependent protein kinase II is both necessary and sufficient to promote lethal ventricular arrhythmias. Methods and results- Mice in which the S2814 Ca/calmodulin-dependent protein kinase II site on RyR2 is constitutively activated (S2814D) develop pathological sarcoplasmic reticulum Ca release events, resulting in reduced sarcoplasmic reticulum Ca load on confocal microscopy. These Ca release events are associated with increased RyR2 open probability in lipid bilayer preparations. At baseline, young S2814D mice have structurally and functionally normal hearts without arrhythmias; however, they develop sustained ventricular tachycardia and sudden cardiac death on catecholaminergic provocation by caffeine/epinephrine or programmed electric stimulation. Young S2814D mice have a significant predisposition to sudden arrhythmogenic death after transverse aortic constriction surgery. Finally, genetic ablation of the Ca/calmodulin-dependent protein kinase II site on RyR2 (S2814A) protects mutant mice from pacing-induced arrhythmias versus wild-type mice after transverse aortic constriction surgery. Conclusions- Our results suggest that Ca/calmodulin-dependent protein kinase II phosphorylation of RyR2 Ca release channels at S2814 plays an important role in arrhythmogenesis and sudden cardiac death in mice with heart failure.

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KW - calcium

KW - calcium-calmodulin-dependent protein kinase type 2

KW - heart failure

KW - ryanodine receptor calcium release channel

KW - sarcoplasmic reticulum

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