Sorafenib induces cardiotoxicity through RBM20-mediated alternative splicing of sarcomeric and mitochondrial genes
Sorafenib induces cardiotoxicity through RBM20-mediated alternative splicing of sarcomeric and mitochondrial genes
复制标题
DOI：
10.1016/j.phrs.2023.107017
复制
发表时间：
2023-11-24
影响因子：
9.3
通讯作者：
Wang，Huan
中科院分区：
文献类型：
--
作者：
Liu，Songming;Yue，Shanshan;Wang，Huan
Sorafenib是一种多靶点酪氨酸激酶抑制剂，是晚期实体瘤的一线治疗药物，但它会诱发许多不良心血管事件，包括心肌梗死和心力衰竭。这些心脏缺陷可以通过对心脏功能至关重要的基因的选择性剪接介导。是否选择性剪接在索拉非尼诱导的心脏毒性中起作用仍不清楚。通过分析和验证索拉非尼处理的大鼠心脏或人心肌细胞的转录组，以确定选择性剪接基因及其对心脏毒性的影响。在大鼠中，索拉非尼引起严重的心脏毒性，左心室收缩压降低，肌节延长，线粒体增大，ATP减少。这与心脏中数百个基因的选择性剪接有关，其中许多是心脏特异性剪接因子RBM20的靶点。索拉非尼抑制大鼠心脏和人心肌细胞中RBM20的表达。RBM20的靶基因SLC25A3和FHOD3的剪接被改变为胎儿同种异构体，功能下降。索拉非尼治疗期间RBM20的上调逆转了SLC25A3和FHOD3的致病剪接，并通过SLC25A3、ATP合成和细胞存活增强了磷酸盐向线粒体的转运。我们设想这种调节可能发生在许多药物诱导的心脏毒性中，并代表了减轻索拉非尼诱导的心脏毒性的潜在药物途径。
Sorafenib, a multi-targeted tyrosine kinase inhibitor, is a first-line treatment for advanced solid tumors, but it induces many adverse cardiovascular events, including myocardial infarction and heart failure. These cardiac defects can be mediated by alternative splicing of genes critical for heart function. Whether alternative splicing plays a role in sorafenib-induced cardiotoxicity remains unclear. Transcriptome of rat hearts or human cardiomyocytes treated with sorafenib was analyzed and validated to define alternatively spliced genes and their impact on cardiotoxicity. In rats, sorafenib caused severe cardiotoxicity with decreased left ventricular systolic pressure, elongated sarcomere, enlarged mitochondria and decreased ATP. This was associated with alternative splicing of hundreds of genes in the hearts, many of which were targets of a cardiac specific splicing factor, RBM20. Sorafenib inhibited RBM20 expression in both rat hearts and human cardiomyocytes. The splicing of RBM20’s targets, SLC25A3 and FHOD3, was altered into fetal isoforms with decreased function. Upregulation of RBM20 during sorafenib treatment reversed the pathogenic splicing of SLC25A3 and FHOD3, and enhanced the phosphate transport into mitochondria by SLC25A3, ATP synthesis and cell survival.We envision this regulation may happen in many drug-induced cardiotoxicity, and represent a potential druggable pathway for mitigating sorafenib-induced cardiotoxicity.