The Loss of p21-Activated Kinase (Pak1) Promotes Atrial Arrhythmic Activity
journal contributionposted on 2018-10-18, 00:00 authored by Jaime DeSantiago, Dan J. Bare, Disha Varma, R. John Solaro, Rishi Arora, Kathrin Banach
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 based on the 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-/- AMs exhibit increased basal and AngII (1 µM)-induced ROS production, sensitive to the NOX inhibitor apocynin (1 µM), 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 the NCX inhibitor KB-R7943 (1 µM) 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: Overall the experiments support that during AF Pak1 stimulation can attenuate NCX dependent Ca2+ overload and trigger activity by suppressing NOX2 dependent ROS production.
The work was supported by grants from the American Heart Association GRNT25700257, the National Institutes of Health HL128330, and HL132871 to KB, HL093490 to RA, and PO1 HL 62426 and to RJS.
CitationDeSantiago, J., Bare, D. J., Varma, D., Solaro, R. J., Arora, R., & Banach, K. (2018). Loss of p21-activated kinase 1 (Pak1) promotes atrial arrhythmic activity. Heart Rhythm, 15(8), 1233-1241. doi:10.1016/j.hrthm.2018.03.041