Second-generation antipsychotics induce cardiotoxicity by disrupting spliceosome signaling: Implications from proteomic and transcriptomic analyses
Second-generation antipsychotics induce cardiotoxicity by disrupting spliceosome signaling: Implications from proteomic and transcriptomic analyses
复制标题
第二代抗精神病药通过破坏剪接体信号传导诱导心脏毒性：蛋白质组学和转录组学分析的意义
DOI：
10.1016/j.phrs.2021.105714
复制
发表时间：
2021-06-10
影响因子：
9.3
通讯作者：
Li, Liliang
中科院分区：
文献类型：
--
作者：
Wang, Jing;Li, Xiaoqing;Li, Liliang
第二代抗精神病药物(SGAs)是临床上用于治疗精神障碍的一线药物。严重的心脏毒性已被广泛报道，从而限制了其临床应用。本研究旨在通过双重组学分析确定SGAs引起心脏毒性的共同机制。给BALB/C小鼠腹腔注射两种具有代表性的SGAs，奥氮平(2.5 mg/kg)和氯氮平(25 mg/kg)，按临床可比剂量分别给予0、7、14和21天。我们的结果表明，两种SGAs均可引起心肌细胞变性、炎症浸润和心肌纤维化，并随着时间的延长而加重。蛋白质组学分析显示，奥氮平和氯氮平治疗的心脏中有22个差异表达(DE)蛋白重叠。通过GO术语分析，这些蛋白质在肌肉收缩、氨基酸代谢和剪接体组装中显著丰富，KEGG分析发现剪接体信号通路是最丰富的途径之一。在22个DE蛋白中，有3个剪接体信号蛋白在动态检测中得到验证，它们的表达与SGAS诱导的心肌纤维化程度显著相关。在剪接体信号失控之后，RNA测序显示SGAS处理后小鼠心脏中的选择性剪接事件显著增加，大量转录变异体的产生导致了对心肌细胞适应和心脏重塑至关重要的多条通路的失控。RNA剪接的特异性抑制剂Pladienolide B成功地纠正了SGAs诱导的选择性剪接，并显著减弱了SGAs诱导的促炎因子的分泌和细胞死亡。我们的研究得出结论，剪接体信号是SGAs心脏毒性的常见途径。药物抑制剪接体信号代表了一种对抗SGAs心脏毒性的新的治疗策略。
Second-generation antipsychotics (SGAs) are first-line drugs that are prescribed for mental disorders in clinic. Severe cardiotoxicity has been widely reported and thus limits their clinical application. This study aimed to identify the common mechanism underlying SGAs-induced cardiotoxicity using dual-omics analyses. Balb/C mice were intraperitoneally injected with two representative SGAs, olanzapine (2.5 mg/kg) and clozapine (25 mg/kg), at clinically comparable doses for 0, 7, 14 and 21 days. Our results showed that both SGAs induced cardiomyocyte degeneration, inflammation infiltration, and cardiac fibrosis, all of which worsened with time. Proteomic analysis revelaed that 22 differentially expressed (DE) proteins overlapped in olanzapine and clozapine-treated hearts. These proteins were significantly enriched in muscle contraction, amino acid metabolism and spliceosomal assembly by GO term analysis and spliceosome signaling was among the top enriched pathways by KEGG analysis. Among the 22 DE proteins, three spliceosome signal proteins were validated in a dynamic detection, and their expression significantly correlated with the extent of SGAs-induced cardiac fibrosis. Following the spliceosome signaling dysregulation, RNA sequencing revealed that alternative splicing events in the mouse hearts were markedly enhanced by SGAs treatments, and the production of vast transcript variants resulted in dysregulation of multiple pathways that are critical for cardiomyocytes adaptation and cardiac remodeling. Pladienolide B, a specific inhibitor of mRNA splicing, successfully corrected SGAs-induced alternative splicing and significantly attenuated the secretion of pro-inflammatory factors and cell deaths induced by SGAs exposure. Our study concluded that the spliceosome signaling was a common pathway driving SGAs cardiotoxicity. Pharmacological inhibition of the spliceosome signaling represents a novel therapeutic strategy against SGAs cardiotoxicity.