Cardiac deficiency of P21-activated kinase 1 promotes atrial arrhythmogenesis in mice following adrenergic challenge.
Eunjeong JungRebecca CapelCongshan JiangElisa VenturiGeorgiana NeaguSarah PearceyYafei ZhouYanmin ZhangMing LeiPublished in: Philosophical transactions of the Royal Society of London. Series B, Biological sciences (2023)
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'.
Keyphrases
- atrial fibrillation
- left atrial
- wild type
- catheter ablation
- left ventricular
- high fat diet induced
- gene expression
- protein kinase
- mitral valve
- high resolution
- percutaneous coronary intervention
- transcription factor
- stem cells
- acute coronary syndrome
- type diabetes
- oral anticoagulants
- oxidative stress
- dna methylation
- climate change
- brain injury
- venous thromboembolism
- insulin resistance
- adipose tissue
- tyrosine kinase
- left atrial appendage
- metabolic syndrome
- direct oral anticoagulants
- blood brain barrier
- human health
- binding protein
- replacement therapy
- smoking cessation
- liver fibrosis