Ibrutinib Promotes Atrial Fibrillation by Disrupting A-Kinase Anchoring Protein 1-Mediated Mitochondrial Quality Surveillance in Cardiomyocytes.

IF 11 1区 综合性期刊 Q1 Multidisciplinary Research Pub Date : 2024-10-29 eCollection Date: 2024-01-01 DOI:10.34133/research.0509
Yukun Li, Xinmeng Liu, Rong Lin, Xiaodong Peng, Xuesi Wang, Fanchao Meng, Shuqi Jin, Wenhe Lv, Xiaoying Liu, Zhuohang Du, Songnan Wen, Rong Bai, Yanfei Ruan, Hao Zhou, Rongjun Zou, Ribo Tang, Nian Liu
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Abstract

Background: Ibrutinib, a potent Bruton's tyrosine kinase inhibitor with marked efficacy against hematological malignancies, is associated with the heightened risk of atrial fibrillation (AF). Although ibrutinib-induced AF is linked to enhanced oxidative stress, the underlying mechanisms remain unclear. Objective: This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF. Methods: We performed in vivo electrophysiology studies using ibrutinib-treated mice, and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms. The effects of A-kinase anchoring protein 1 (AKAP1) depletion on mitochondrial quality surveillance (MQS) were evaluated using both in vivo and ex vivo AKAP1 overexpression models. Results: Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice, leading to inducible AF, atrial fibrosis, and mitochondrial fragmentation. These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1. In ibrutinib-treated atrial myocytes, AKAP1 down-regulation promoted dynamin-related protein 1 (DRP1) translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637, thereby mediating excessive mitochondrial fission. Impaired MQS was also suggested by defective mitochondrial respiration, mitochondrial metabolic reprogramming, and suppressed mitochondrial biogenesis, accompanied by excessive oxidative stress and inflammatory activation. The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system. Conclusions: Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF, which explains the previously observed reactive oxygen species overproduction. Hence, AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.

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伊布替尼通过破坏心肌细胞中A-激酶锚定蛋白1介导的线粒体质量监测促进心房颤动
背景:伊布替尼是一种强效的布鲁顿酪氨酸激酶抑制剂,对血液恶性肿瘤有显著疗效,但与心房颤动(房颤)风险增加有关。虽然伊布替尼诱导的房颤与氧化应激增强有关,但其潜在机制仍不清楚。研究目的本研究旨在探讨伊布替尼诱导房颤的分子机制和调控靶点。方法我们利用伊布替尼处理的小鼠进行了体内电生理学研究,然后利用蛋白质组和单细胞转录组分析确定了潜在的靶点和机制。使用体内和体外 AKAP1 过度表达模型评估了 A 激酶锚定蛋白 1(AKAP1)耗竭对线粒体质量监控(MQS)的影响。结果伊布替尼处理的小鼠心房AKAP1表达明显减少,导致诱发房颤、心房纤维化和线粒体破碎。在伊布替尼治疗小鼠注射携带Akap1的腺相关病毒的过表达模型中,这些病理变化得到了有效缓解。在伊布替尼处理的心房肌细胞中,AKAP1的下调促进了Dynamin相关蛋白1(DRP1)在Ser637处的去磷酸化,从而促进了DRP1向线粒体的转位,从而介导了线粒体的过度分裂。线粒体呼吸缺陷、线粒体代谢重编程和线粒体生物生成受抑制,并伴有过度氧化应激和炎症激活,也表明 MQS 受损。伊布替尼介导的 MQS 干扰可通过诱导表达 AKAP1 慢病毒系统得到明显改善。结论我们的研究结果强调了 AKAP1 介导的 MQS 干扰在伊布替尼诱导的房颤中的关键作用,这也解释了之前观察到的活性氧过量产生的原因。因此,可以利用激活 AKAP1 来预防和治疗伊布替尼诱导的房颤。
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来源期刊
Research
Research Multidisciplinary-Multidisciplinary
CiteScore
13.40
自引率
3.60%
发文量
0
审稿时长
14 weeks
期刊介绍: Research serves as a global platform for academic exchange, collaboration, and technological advancements. This journal welcomes high-quality research contributions from any domain, with open arms to authors from around the globe. Comprising fundamental research in the life and physical sciences, Research also highlights significant findings and issues in engineering and applied science. The journal proudly features original research articles, reviews, perspectives, and editorials, fostering a diverse and dynamic scholarly environment.
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