The Loss of p21-Activated Kinase (Pak1) Promotes Atrial Arrhythmic Activity

Background: Atrial fibrillation (AF) is initiated through arrhythmic atrial excitation from outside the sinus node or remodeling of atrial tissue that allows reentry of excitation. Angiotensin II (AngII) has been implicated in initiation and maintenance of AF through changes in Ca2+ handling and production of reactive oxygen species (ROS).

Objective: We aimed to determine the role of Pak1, a downstream target in the AngII signaling cascade, in atrial electrophysiology and arrhythmia. Method: WT and Pak1-/- mice were used to determine atrial function in vivo, on the organ and cellular level by quantification of electrophysiological and Ca2+-handling properties.

Results: We demonstrate that reduced Pak1 activity increases the inducibility of atrial arrhythmia in vivo and in vitro. On the cellular level, Pak1-/- atrial myocytes (AMs) exhibit increased basal and AngII (1 mM)-induced ROS production, sensitivity to the NOX2 inhibitors gp91ds-tat and apocynin (1 mM), and enhanced membrane translocation of Rac1 that is part of the multi-molecular NOX2 complex. Upon stimulation with AngII, Pak1-/- AMs exhibit an exaggerated increase in [Ca2+]i, and arrhythmic events that were sensitive to NCX inhibitors (KB-R7943, SEA0400; 1 mM) and suppressed in AMs from NOX2 deficient (gp91phox-/-) mice. Pak1 stimulation (FTY720: 200 nM) in WT AMs and AMs from a canine model of ventricular tachypacing-induced AF, prevented AngII-induced arrhythmic Ca2+ overload, by attenuating NCX activity in a NOX2 dependent manner. 

Conclusion: The experiments support that Pak1 stimulation can attenuate NCX-dependent Ca2+ overload and prevent triggered arrhythmic activity by suppressing NOX2-dependent ROS production.