lncRNA Kcnq1ot1改善三氧化二砷心脏毒性的新机制

Arsenic trioxide is one of the most efficient therapeutic drugs for acute promyelocytic leukemia (APL), its clinical application was limited by cardiotoxicity. However, the mechanism of arsenic trioxide-induced cardiotoxicity has not been full elucidated, resulting in a lake of effective intervention targets. Arsenic trioxide-induced cardiac toxicity was similar to that in the aging heart. Our study found that long noncoding RNA (lncRNA) Kcnq1ot1 was down-regulated in the aging heart. Arsenic trioxide could also inhibit the expression of lncRNA Kcnq1ot1, which was attenuated by co-administration of anti-aging drugs. Bioinformatics prediction showed that lncRNA Kcnq1ot1 could increase the expression of Sirt1 through competitive binding with miR-34a. This study was conducted to investigate the role of lncRNA Kcnq1ot1 in arsenic trioxide-induced cardiotoxicity using gene overexpression and interference techniques both in vivo and in vitro, and to clarify the related molecular mechanisms. The innovation of this study is to propose the essence of arsenic trioxide-induced cardiotoxicity is to induce heart aging, reveal a new lncRNA Kcnq1ot1/miR-34a/Sirt1 involved mechanism to alleviate arsenic trioxide-induced cardiotoxicity, and provide new ideas for the prevention and treatment of antitumor drugs-induced cardiotoxicity.

三氧化二砷是治疗急性早幼粒细胞白血病的特效药，但心脏毒性限制了其临床应用。然而，三氧化二砷心脏毒性机制尚未阐明，导致缺乏有效的干预靶点。三氧化二砷诱导心脏毒性的表现与心脏衰老相似。我们研究发现，长非编码RNA（lncRNA）Kcnq1ot1在心脏衰老时表达下调。三氧化二砷同样可抑制lncRNA Kcnq1ot1表达，而具有抗衰老作用的药物可逆转三氧化二砷的作用。生物信息学预测发现，lncRNA Kcnq1ot1可通过竞争性结合miR-34a增加具有抗衰老作用的Sirt1表达。本研究拟于在体和离体水平证实应用基因过表达和干扰技术系统阐明lncRNA Kcnq1ot1在三氧化二砷诱导心脏毒性中的作用及机制。创新点在于首次提出三氧化二砷心脏毒性的本质是诱导心脏衰老，揭示激活lncRNA Kcnq1ot1/miR-34a/Sirt1通路改善心脏毒性的新机制，为抗肿瘤药心脏毒性的防治提供新思路。

三氧化二砷是治疗急性早幼粒细胞白血病的特效药，但心脏毒性限制了其临床应用。然而，三氧化二砷心脏毒性机制尚未完全阐明，导致缺乏有效的干预靶点。因此，揭示三氧化二砷心脏毒性机制，提出有效防治策略对促进药物临床合理应用具有重要意义。长链非编码RNA（long noncoding RNA，lncRNA）在多种病理生理过程的关键调控作用逐渐被揭示。我们的前期研究发现，三氧化二砷可通过抑制lncRNA Kcnq1ot1诱导长QT间期综合征。本项目进一步揭示非编码RNA在三氧化二砷心脏毒性中的作用及毒性防治中的意义。主要发现点如下：① 证实lncRNA Kcnq1ot1/miR-34a-5p/Sirt1通路参与三氧化二砷诱导的心脏毒性。② 发现普萘洛尔对三氧化二砷诱导的心脏毒性具有保护作用，该作用与上调lncRNA Kcnq1ot1有关。③ 应用RNA测序（RNA-sequencing，RNA-seq）技术获取三氧化二砷心脏毒性相关编码和非编码基因表达谱，并应用生物信息学方法分析，提出潜在的干预靶点。本研究揭示非编码RNA介导的三氧化二砷心脏毒性机制，为开发基于非编码RNA的三氧化二砷联合用药策略提供新思路。