Key result
Cardiac deficiency of Pak1 in mice promotes atrial arrhythmogenesis under adrenergic stress, associated with altered calcium homeostasis and increased RyR2 channel open probability.
Why the study?
Pak1 signalling plays a vital and protective role in the heart, but the phenotypes of Pak1 deficiency in the cardiac atria have not been well explored.
Cardiac deficiency of Pak1 promotes atrial arrhythmogenesis under adrenergic stress via modifications of key molecules critical to calcium homeostasis.
Pak1 loss promotes atrial arrhythmias in mice; hypothesis-generating for Pak1-targeted AF prevention pending human studies.
P21-activated kinase 1 (Pak1) signalling plays a vital and overall protective role in the heart. However, the phenotypes of Pak1 deficiency in the cardiac atria have not been well explored. In this study, Pak1 cardiac-conditional knock-out (cKO) mice were studied under baseline and adrenergic challenge conditions. Pak1 cKO mice show atrial arrhythmias including atrial fibrillation (AF) in vivo , detected during anaesthetized electrocardiography without evidence of interstitial fibrosis upon Masson's trichrome staining. Optical mapping of left atrial preparations from Pak1 cKO mice revealed a higher incidence of Ca 2+ and action potential alternans under isoprenaline challenge and differences in baseline action potential and calcium transient characteristics. Type-2 ryanodine receptor (RyR2) channels from Pak1 cKO hearts had a higher open probability than those from wild-type. Reverse transcription-quantitative polymerase chain reaction and Western blotting indicated that pCamkII δ and RyR2 are highly phosphorylated at baseline in the atria of Pak1 cKO mice, while the expression of Slc8a2 and Slc8a3 as a Na + –Ca 2+ exchanger, controlling the influx of Ca 2+ from outside of the cell and efflux of Na + from the cytoplasm, are augmented. Chromatin immunoprecipitation study showed that pCreb1 interacts with Slc8a2 and Slc8a3 . Our study thus demonstrates that deficiency of Pak1 promotes atrial arrhythmogenesis under adrenergic stress, probably through post-translational and transcriptional modifications of key molecules that are critical to Ca 2+ homeostasis. This article is part of the theme issue ‘The heartbeat: its molecular basis and physiological mechanisms’.
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Jung et al. (2023) studied Atrial arrhythmogenesis. Pak1 cardiac-conditional knock-out vs. Wild-type was evaluated on Atrial arrhythmias including atrial fibrillation (AF) in vivo and cellular electrophysiological changes. Cardiac deficiency of Pak1 in mice promotes atrial arrhythmogenesis under adrenergic stress, associated with altered calcium homeostasis and increased RyR2 channel open probability.
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