Increased Risk Of Atrial Fibrillation With Attenuated Activity Of P21-Activated Kinase
BIOPHYSICAL JOURNAL(2014)
摘要
The mechanisms underlying atrial fibrillation (AF) are not fully understood. In a canine model of chronic atrial fibrillation (AF) we determined that the p21-activated kinase1 (Pak1) was down-regulated compared to animals in sinus rhythm. The down-regulation was mimicked in an in-vitro model of AF (atrial myocytes + Angiotensin II (AngII: 1μM, 24 h) leading us to hypothesize that attenuated Pak1 activity enhances atrial arrhythmic activity. ECG recordings in WT and Pak1-KO mice performed under control conditions and during stimulation with AngII or Carbachol (CCh: 150 ng/g) revealed spontaneous atrial arrhythmic events in Pak1-KO mice. In field stimulated isolated atrial myocytes (AM) an increased number of delayed after-depolarizations was determined (DADs WT: 14%; Pak1-KO: 39% of cells). AMs with attenuated Pak1 activity (Pak1-KO or WT + IPA3 : 10μM) exhibited an exaggerated increase in AngII induced ROS production (DCF, ΔF/F0: WT(ctl) 1.33±0.07, WT(IPA3) 1.77±0.04 , Pak1-KO 1.77±0.08 ) that was attenuated in the presence of the NOX2 inhibitor apocynin (100 μM). The exaggerated AngII induced increase in Ca transient amplitude (ΔF/F0: WT(ctl) 2.6±0.2, WT(AngII) 3.4±0.4, Pak1-KO(ctl) 2.7±0.3, Pak1-KO(AngII) 4.1±0.4; p < 0.05) was also suppressed by NOX2 inhibition despite the fact that the increase in Ca depended on its release from inositol 1,4,5-trisphosphate sensitive stores (2-APB: 2μM). Pak1 stimulation in WT cells by FTY720 (200 nM) attenuated the AngII induced ROS production as well as the increase in Ca transients. In conclusion, attenuated Pak1 activity in atrial tissue increases the likelihood of AF. Pak1 stimulation attenuates NOX2 dependent ROS production and the subsequent facilitation of IP3R mediated Ca release.
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关键词
Atrial Fibrillation
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