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Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection
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The role of P21-activated kinase (Pak1) in sinus node function.

Carlos H Pereira1, Dan J Bare2, Paola C Rosas3

  • 1Dept. of Internal Medicine/Cardiology, Rush University Medical Center, 1750 W. Harrison St., Chicago, IL 60612, USA; Biological Science Center, Department of Physiology, Av. Cel Francisco H. dos Santos 100, 19031 Centro Politécnico-Curitiba, Brazil.

Journal of Molecular and Cellular Cardiology
|April 22, 2023
PubMed
Summary

p21-activated kinase 1 (Pak1) deficiency slows heart rate by reducing HCN channel expression in the sinoatrial node. Restoring Pak1 activity may treat bradycardia and atrial fibrillation susceptibility.

Keywords:
Atrial fibrillationHCN channelMembrane clockReactive oxygen speciesSinoatrial nodep21-activated kinase 1

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Methods for the Isolation, Culture, and Functional Characterization of Sinoatrial Node Myocytes from Adult Mice
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Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Cardiac Electrophysiology

Background:

  • Sinoatrial node (SAN) dysfunction (SND) and atrial fibrillation (AF) often coexist, with SND patients having a 4.2-fold higher risk of new-onset AF.
  • In atrial muscle, reduced p21-activated kinase 1 (Pak1) activity elevates AF risk via increased reactive oxygen species (ROS) production.
  • The role of Pak1-mediated ROS regulation in SAN function remains unclear.

Purpose of the Study:

  • To investigate the role of Pak1 in regulating SAN activity and heart rate.
  • To test the hypothesis that Pak1 activity maintains SAN function by modulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channel expression.

Main Methods:

  • Quantified intrinsic sinus rhythm in wild-type (WT) and Pak1-deficient (Pak1-/-) mice using in vivo and ex vivo Langendorff perfusion methods.
  • Assessed the contribution of the Ca2+ clock and membrane clock (using Ivabradine, an HCN channel blocker) to pacemaker activity.
  • Measured HCN4 expression in atrial tissue and evaluated rescue strategies including class II HDAC inhibition, ROS scavenging, and ERK1/2 inhibition.

Main Results:

  • Pak1-/- mice exhibited significantly reduced heart rate compared to WT mice, both in vivo and in isolated hearts.
  • The difference in SAN activity between genotypes was abolished by Ivabradine, indicating a critical role for HCN channels.
  • Reduced HCN4 expression was observed in Pak1-/- atria, and this deficit was reversible with LMK235, TEMPOL, or SCH772984.
  • No sex-specific differences in Pak1-dependent SAN regulation were found.

Conclusions:

  • Pak1 plays a crucial role in maintaining SAN function and heart rate, primarily through regulating HCN channel expression.
  • Pak1 acts as a regulator of class II histone deacetylases (HDACs) and influences ROS and ERK1/2 signaling pathways.
  • Targeting Pak1 represents a potential therapeutic strategy for mitigating SAN bradycardia and reducing susceptibility to atrial fibrillation.