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The oxidation-resistant CaMKII-MM281/282VV mutation does not prevent arrhythmias in CPVT1

Mani Sadredini1, Ravinea Manotheepan1, Stephan E Lehnart2,3,4

  • 1Institute for Experimental Medical Research and KG Jebsen Cardiac Research Centre, Oslo University Hospital and University of Oslo, Oslo, Norway.

Physiological Reports
|September 24, 2021
PubMed

Insights

Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) involves RyR2 mutations causing Ca2+ leak. Antioxidant treatment reduced arrhythmias in CPVT1 mice, but an oxidation-resistant CaMKII form did not offer protection, suggesting other targets are involved.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Genetics of Arrhythmias

Background:

  • Catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) is an inherited arrhythmia disorder.
  • CPVT1 arises from mutations in cardiac ryanodine receptors (RyR2), leading to increased calcium (Ca2+) leak upon beta-adrenergic stimulation.
  • Previous research indicated exercise training prevents CPVT1 arrhythmias, potentially by reducing Ca2+/calmodulin-dependent protein kinase type II (CaMKII) oxidation.

Purpose of the Study:

  • To investigate if an oxidation-resistant form of CaMKII can protect against arrhythmias in mice with a CPVT1-causing RyR2 mutation (RyR2-R2474S).
  • To determine if preventing CaMKII oxidation has an antiarrhythmic effect in a CPVT1 mouse model.
  • To explore alternative oxidation-sensitive targets responsible for the antiarrhythmic effects of antioxidant treatment.

Main Methods:

  • Created a double transgenic mouse model (RyR2-RS/MMVV) by crossing RyR2-R2474S mutant mice with mice expressing an oxidation-resistant CaMKII variant (CaMKII-MM281/282VV).
  • Utilized telemetric electrocardiogram (ECG) monitoring to assess arrhythmia incidence and severity in wild-type, RyR2-RS, and RyR2-RS/MMVV mice.
  • Examined beta-adrenoceptor stimulation-induced Ca2+ waves in isolated cardiomyocytes from these mouse models.

Main Results:

  • Both RyR2-RS and RyR2-RS/MMVV mice exhibited increased ventricular tachycardia and arrhythmia scores compared to wild-type mice after beta-adrenoceptor challenge or exercise plus challenge.
  • No significant differences in arrhythmia incidence were observed between RyR2-RS and RyR2-RS/MMVV mice.
  • Beta-adrenoceptor stimulation-induced Ca2+ waves were not reduced in RyR2-RS/MMVV cardiomyocytes compared to RyR2-RS.

Conclusions:

  • Antioxidant treatment effectively reduces arrhythmogenic Ca2+ waves in CPVT1 mouse cardiomyocytes.
  • An oxidation-resistant CaMKII variant does not confer protection against arrhythmias or Ca2+ waves in CPVT1 mice.
  • The antiarrhythmic benefits of antioxidant treatment in CPVT1 may involve oxidation-sensitive targets other than CaMKII.
Keywords:
CPVTCaMKIIRyR2arrhythmiasoxidation

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