Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes.
Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes.
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DOI：
10.1186/s12916-023-02838-2
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发表时间：
2023-04-17
期刊：
影响因子：
9.3
通讯作者：
Han, Sen
中科院分区：
文献类型：
--
作者：
Wang, Huan;Wang, Yiming;Li, Jiongyuan;He, Ziyi;Boswell, Sarah A.;Chung, Mirra;You, Fuping;Han, Sen
酪氨酸激酶抑制剂 (TKI) 是一种抗癌疗法，通常用于长期治疗。许多这些治疗方法会导致心脏毒性，且治愈率有限。我们的目的是阐明 TKI 引起的心脏毒性的分子机制，从而找到治疗心脏不良并发症的潜在靶点。选择了八种具有不同心脏毒性水平的 TKI。对不同剂量和时间的人类心肌细胞对 TKI 的表型和转录组反应进行了分析。调节三种 TKI 诱导的心脏毒性的应激反应和信号通路在心肌细胞和大鼠心脏中得到了验证。通过测量八种 TKI 对细胞活力、收缩性和呼吸的影响确定的毒性等级与数据库或文献中的结果基本一致，表明人心肌细胞是研究心脏毒性的良好细胞模型。当对人类心肌细胞中具有不同毒性水平的选定 TKI 治疗的转录组进行测量时，数据被分为 7 个簇，其中主要是单一药物簇。药物对转录组的特异性作用超过了剂量、时间或毒性依赖性作用。包含三种 TKI（阿法替尼、普纳替尼和索拉非尼）的两个簇具有内质网应激 (ERS) 的顶部富集途径。所有三种 TKI 都会在大鼠原代心肌细胞中诱导 ERS，并且 ponatinib 在接受 7 天药物治疗的大鼠心脏中激活 ERS 下游的 IRE1α-XBP1s 轴。为了寻找 ERS 的潜在触发因素，我们发现这三种 TKI 会诱导短暂的活性氧，随后发生脂质过氧化。抑制 ERS 下游的 PERK 或 IRE1α 可以阻断 TKI 诱导的心脏损伤，表现为心脏胎儿和促炎基因的诱导，而不会导致更多的细胞死亡。我们的数据包含有关人类心肌细胞对八种 TKI 的表型和转录反应的丰富信息，揭示了调节心脏毒性的潜在分子机制。内质网应激由多种 TKI 激活，并通过促进促炎因子和心脏胎儿基因的表达导致心脏毒性。内质网应激诱导的炎症是减轻帕纳替尼和索拉非尼诱导的心脏毒性的有前途的治疗靶点。在线版本包含可在 10.1186/s12916-023-02838-2 获取的补充材料。
Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity. The online version contains supplementary material available at 10.1186/s12916-023-02838-2.
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32.4
作者：
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