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p21-Activated kinase1 (Pak1) is a negative regulator of NADPH-oxidase 2 in ventricular myocytes

Jaime DeSantiago1, Dan J Bare1, Lei Xiao2

  • 1Center for Cardiovascular Research, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60612, USA; Department of Medicine, Section of Cardiology, University of Illinois at Chicago, 840 S. Wood Street, Chicago, IL 60612, USA.

Journal of Molecular and Cellular Cardiology
|January 2, 2014
PubMed

Insights

p21-activated kinase (Pak1) deficiency in heart cells increases calcium overload and arrhythmias during ischemia. Pak1 normally suppresses reactive oxygen species (ROS) and sodium-calcium exchanger (NCX) activity, preventing these issues.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Cell Physiology

Background:

  • Ischemic conditions reduce p21-activated kinase (Pak1) activity, leading to increased cardiac arrhythmias.
  • Arrhythmias during ischemia are linked to altered cellular ion balance and calcium handling.
  • Pak1's role in regulating these changes is not fully understood.

Purpose of the Study:

  • To investigate the mechanism by which Pak1 influences arrhythmic activity generation during simulated ischemia.
  • To determine Pak1's role in regulating calcium handling and reactive oxygen species (ROS) production in ventricular myocytes (VMs).

Main Methods:

  • Utilized isolated mouse ventricular myocytes (VMs) genetically deficient for Pak1 (Pak1(-/-)).
  • Simulated ischemic conditions and measured intracellular calcium ([Ca(2+)]i) transients, ROS levels, and sodium-calcium exchanger (NCX) activity.
  • Employed pharmacological inhibitors for NCX, ROS, and Rac1, as well as genetic models for NADPH oxidase 2 (NOX2).

Main Results:

  • Pak1(-/-) VMs showed exaggerated intracellular calcium ([Ca(2+)]i) overload and spontaneous calcium release events during simulated ischemia.
  • This calcium overload was suppressed by NCX blockers, ROS scavengers, and Rac1 inhibitors.
  • Pak1 deficiency led to increased cellular ROS production, dependent on NADPH oxidase 2 (NOX2).
  • Pak1(-/-) VMs exhibited enhanced NCX activity, driven by NOX2-induced ROS.

Conclusions:

  • Pak1 acts as a critical negative regulator of NOX2-dependent ROS production in cardiac myocytes.
  • Reduced Pak1 activity promotes ROS-mediated NCX stimulation, leading to calcium overload.
  • This mechanism predisposes ventricular myocytes to arrhythmias under ischemic conditions, even before significant excitation-contraction coupling changes are evident.
Keywords:
ArrhythmiaCardiomyocyteExcitation–contraction couplingIschemiaSodium calcium exchangerp21-Activated kinase 1

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