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Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
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Inositol Trisphosphate Receptors and Nuclear Calcium in Atrial Fibrillation

Xiao-Yan Qi1, Faezeh Vahdati Hassani1, Dennis Hoffmann2

  • 1Medicine, Montreal Heart Institute, Université de Montréal, Canada (X.-Y.Q., F.V.H., J.X., F.X., L.R.V., D.D., S.N.).

Circulation Research
|December 30, 2020
PubMed
Abstract

Insights

Atrial fibrillation (AF) increases nuclear calcium levels in heart cells by upregulating IP3R1, driven by miR-26a. This impacts CaMKII-HDAC4 signaling and reduces L-type calcium currents, contributing to AF mechanisms.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Arrhythmia Mechanisms

Background:

  • Atrial fibrillation (AF) is the most common arrhythmia, yet its underlying mechanisms remain unclear.
  • Nuclear calcium (Ca2+) dynamics are critical for gene expression but poorly understood in AF.
  • The role of nucleoplasmic Ca2+ and CaMKII signaling in AF pathogenesis requires elucidation.

Purpose of the Study:

  • To investigate how AF affects atrial cardiomyocyte nuclear Ca2+ levels ([Ca2+]Nuc) and CaMKII signaling pathways.
  • To identify the molecular regulators involved in AF-induced nuclear Ca2+ dysregulation.
  • To explore the functional consequences of these changes on cardiomyocyte function.

Main Methods:

  • Isolated atrial cardiomyocytes from control and AF dogs were used for Ca2+ measurements via confocal microscopy.
  • Inositol-trisphosphate receptor (IP3R) stimulation and blockade were employed to assess Ca2+ flux.
  • Protein expression and phosphorylation of IP3R1, CaMKII, and HDAC4 were analyzed using immunohistochemistry and immunoblotting.
  • Experiments included cardiomyocyte tachypacing and microRNA analysis (miR-26a).

Main Results:

  • AF increased both diastolic and resting nuclear Ca2+ ([Ca2+]Nuc) in atrial cardiomyocytes.
  • AF upregulated nuclear IP3R1 and phosphorylated CaMKII, while decreasing the nuclear/cytosolic ratio of HDAC4.
  • IP3R1 upregulation, driven by decreased miR-26a, was identified as a key mechanism.
  • These changes mimicked AF-induced decreases in L-type calcium current.

Conclusions:

  • AF elevates atrial cardiomyocyte nuclear Ca2+ via IP3R1 upregulation, involving miR-26a.
  • This leads to altered IP3R1-CaMKII-HDAC4 signaling, impacting cardiomyocyte function.
  • The findings provide novel insights into AF mechanisms and potential therapeutic targets.
Keywords:
arrhythmiasatrial fibrillationcalciumheart diseasesinositol

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