Febuxostat Increases Ventricular Arrhythmogenesis Through Calcium Handling Dysregulation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Febuxostat Increases Ventricular Arrhythmogenesis Through Calcium Handling Dysregulation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
复制标题
非布索坦通过人诱导多能干细胞来源的心肌细胞中的钙处理失调来增加室性心律失常的发生
DOI：
10.1093/toxsci/kfac073
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发表时间：
2022-07-22
影响因子：
3.8
通讯作者：
Chen，Minglong
中科院分区：
文献类型：
--
作者：
Zhu，Yue;Zheng，Bingyu;Chen，Minglong
非布司他是一种黄嘌呤氧化酶抑制剂，用于减少尿酸的形成和预防痛风发作。先前的研究表明，与别嘌呤醇（另一种抗高尿酸血症药物）相比，非布司他与更高的心血管事件（包括心房颤动）风险相关。然而在我们的临床实践中，我们发现了2例非布司他相关的室性心动过速（VT）事件。非布司他对人心肌细胞的致心律失常作用及其机制尚不清楚。在这项研究中，我们采用实时细胞分析和钙瞬变技术来研究非布司他对人诱导多能干细胞来源的心肌细胞（hiPSC-CMs）的细胞毒性和电生理特性的影响。10 μM的非布司他处理对细胞活力没有毒性。然而，48小时非布司他暴露会产生剂量依赖性的不规则钙瞬态增加和钙瞬态幅度降低。此外，RNA-seq分析表明，非布司他处理组MAPK信号通路富集，尤其是蛋白激酶c-Jun n -末端激酶（JNK）。3种主要蛋白激酶的Western blotting结果表明，JNK活化与非布司他诱导的心律失常有关，而与细胞外信号调节激酶（ERK）或p38无关。JNK抑制剂SP600125可以改善非布司他治疗的hiPSC-CMs的功能失调钙动力学。总之，我们的研究表明，非布司他通过钙动力学失调增加室性心律失常的易感性。
Febuxostat is a xanthine oxidase inhibitor used to reduce the formation of uric acid and prevent gout attacks. Previous studies have suggested that febuxostat was associated with a higher risk of cardiovascular events, including atrial fibrillation, compared with allopurinol, another anti-hyperuricemia drug. Whereas in our clinical practice, we identified 2 cases of febuxostat-associated ventricular tachycardia (VT) events. The proarrhythmogenic effects of febuxostat on human cardiomyocytes and underlined mechanisms remain poorly understood. In this study, we employed real-time cell analysis and calcium transient to investigate the effects of febuxostat on the cytotoxicity and electrophysiology properties of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Up to 10 μM febuxostat treatment did not show toxicity to cell viability. However, 48-h febuxostat exposure generated dose-dependent increased irregular calcium transients and decreased calcium transient amplitude. Furthermore, RNA-seq analysis indicated that the MAPK signaling pathway was enriched in the febuxostat-treated group, especially the protein kinases c-Jun N-terminal kinase (JNK). Western blotting of 3 main protein kinases demonstrated that JNK activation is related to febuxostat-induced arrhythmia rather than extracellular signal regulated kinases (ERK) or p38. The dysfunctional calcium dynamics of febuxostat-treated hiPSC-CMs could be ameliorated by SP600125, the inhibitor of JNK. In conclusion, our study demonstrated that febuxostat increases the predisposition to ventricular arrhythmia by dysregulating calcium dynamics.