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Conditional Up-Regulation of SERCA2a Exacerbates RyR2-Dependent Ventricular and Atrial Arrhythmias

Bin Liu1,2, Qing Lou1, Heather Smith2

  • 1Davis Heart and Lung Research Institute and Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH 43210, USA.

International Journal of Molecular Sciences
|April 9, 2020
PubMed

Insights

Upregulating SERCA2a in mice with hyperactive ryanodine receptor 2 (RyR2) worsened cardiac arrhythmias. This exacerbation was linked to increased diastolic calcium release events, suggesting a detrimental interaction between SERCA2a and RyR2 in heart rhythm disorders.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Ryanodine receptor 2 (RyR2) and SERCA2a are critical for cardiac calcium cycling.
  • Dysregulation of these proteins is implicated in heart disease and arrhythmias.
  • The interplay between RyR2 and SERCA2a in disease pathogenesis is not fully understood.

Purpose of the Study:

  • To investigate the impact of SERCA2a upregulation on arrhythmogenesis in a mouse model with hyperactive RyR2.
  • To elucidate the consequences of combined SERCA2a and RyR2 dysregulation on cardiac function.

Main Methods:

  • Generation of a conditional mouse model by crossbreeding calsequestrin 2 (CASQ2) knock-out mice with doxycycline-inducible SERCA2a transgenic mice.
  • In-vivo electrocardiogram (ECG) studies to assess arrhythmias.
  • Confocal microscopy of atrial and ventricular myocytes.
  • Deep RNA sequencing to identify gene expression changes.

Main Results:

  • SERCA2a overexpression significantly exacerbated both ventricular and atrial arrhythmias compared to controls.
  • Upregulation of SERCA2a increased the frequency of diastolic calcium release events in myocytes.
  • RNA sequencing revealed altered expression of genes, including Ppp1r13l, Clcn1, and Agt, previously associated with arrhythmias.

Conclusions:

  • Conditional SERCA2a upregulation worsens RyR2-mediated cardiac arrhythmias.
  • The exacerbation is likely due to increased diastolic calcium release.
  • This study highlights a detrimental interaction between SERCA2a and hyperactive RyR2 in promoting arrhythmias.
Keywords:
and ec-coupling 4arrhythmia 1calcium channel 2calcium signaling 3

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