Atrial fibrillation (AF) occurs in up to 11% of cancer patients treated with ibrutinib. The pathophysiology of ibrutinib promoted AF is complicated, as there are multiple interactions involved; the detailed molecular mechanisms underlying this are still unclear. Here, we aimed to determine the electrophysiological and molecular mechanisms of burst-pacing-induced AF in ibrutinib-treated mice. The results indicated differentially expressed proteins in ibrutinib-treated mice, identified through proteomic analysis, were found to play a role in oxidative stress-related pathways. Finally, treatment with an inhibitor of NADPH oxidase (NOX) prevented and reversed AF development in ibrutinib-treated mice. It was showed that the related protein expression of reactive oxygen species (ROS) in the ibrutinib group was significantly increased, including NOX2, NOX4, p22-phox, XO and TGF-β protein expression. It was interesting that ibrutinib group also significantly increased the expression of ox-CaMKII, p-CaMKII (Thr-286) and p-RyR2 (Ser2814), causing enhanced abnormal sarcoplasmic reticulum (SR) Ca2+ release and mitochondrial structures, as well as atrial fibrosis and atrial hypertrophy in ibrutinib-treated mice, and apocynin reduced the expression of these proteins. Ibrutinib-treated mice were also more likely to develop AF, and AF occurred over longer periods. In conclusion, our study has established a pathophysiological role for ROS signaling in atrial cardiomyocytes, and it may be that ox-CaMKII and p-CaMKII (Thr-286) are activated by ROS to increase AF susceptibility following ibrutinib treatment. We have also identified the inhibition of NOX as a potential novel AF therapy approach.
Keywords: Atrial fibrillation; Electrical remodeling; Ibrutinib; Reactive oxygen species; Structural remodeling.
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