Loss of p21-activated kinase 1 (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 the 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 p21-activated kinase 1 (Pak1), a downstream target in the AngII signaling cascade, in atrial electrophysiology and arrhythmia. METHODS Wild-type 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 μM)-induced ROS production, sensitivity to the NADPH oxidase-2 (NOX2) inhibitors gp91ds-tat and apocynin (1 μM), and enhanced membrane translocation of Ras-related C3 substrate 1 (Rac1) that is part of the multimolecular NOX2 complex. Upon stimulation with AngII, Pak1-/- AMs exhibit an exaggerated increase in the intracellular Calcium concentration ([Ca2+]i) and arrhythmic events that were sensitive to sodium-calcium exchanger (NCX) inhibitors (KB-R7943 and SEA0400; 1 μM) and suppressed in AMs from NOX2-deficient (gp91phox-/-) mice. Pak1 stimulation (FTY720; 200 nM) in wild-type 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 experimental results support that Pak1 stimulation can attenuate NCX-dependent Ca2+ overload and prevent triggered arrhythmic activity by suppressing NOX2-dependent ROS production.

• Publication year

  2018

• Venue

  Heart Rhythm

• Publication date

  2018-08-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.hrthm.2018.03.041PMID 29625277PMCID PMC7017889
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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