长链非编码 RNA KCNQ1OT1 通过靶向心力衰竭中的 FUS 促进心肌细胞凋亡。
LncRNA KCNQ1OT1 contributes to cardiomyocyte apoptosis by targeting FUS in heart failure.
机构信息
Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China.
Department of Cardiology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, Zhejiang Province, China.
出版信息
Exp Mol Pathol. 2020 Aug;115:104480. doi: 10.1016/j.yexmp.2020.104480. Epub 2020 Jun 2.
Long noncoding RNAs (lncRNAs) have recently been recognized as the important regulators in cardiac diseases. This study was aimed to investigate the role and molecular mechanism of lncRNA KCNQ1OT1 in regulating cardiomyocyte apoptosis in heart failure (HF). The mouse model of HF was induced by doxorubicin (ADR). Cell apoptosis was detected by Hoechst and TUNEL staining. Molecule expressions were determined by qRT-PCR and western blot. The interaction between KCNQ1OT1 and Fused in sarcoma (FUS) was assessed by RNA immunoprecipitation (RIP) and RNA pull-down assays. KCNQ1OT1 was up-regulated in the myocardial tissues of HF mice and the ADR-stimulated mouse myocardial cell line (HL-1). KCNQ1OT1 overexpression promoted apoptosis of ADR-stimulated HL-1 cells, while KCNQ1OT1 knockdown caused the opposite effect. The RIP and RNA pull-down results showed that KCNQ1OT1 - bound to FUS and negatively regulated its protein level. Knockdown of FUS inhibited apoptosis of ADR-stimulated HL-1 cells and reversed the effect of KCNQ1OT1 overexpression on cardiomyocyte apoptosis. In vivo experiment showed that KCNQ1OT1 ovexpression improved myocardial histopathological changes, reduced myocardial fibrosis areas, down-regulated FUS expression, and inhibited cell apoptosis of HF mice. In conclusion, KCNQ1OT1 facilitates cardiomyocyte apoptosis by - targeting FUS in ADR-induced HF.
长链非编码 RNA（lncRNA）最近被认为是心脏疾病的重要调控因子。本研究旨在探讨 lncRNA KCNQ1OT1 在调节心力衰竭（HF）中心肌细胞凋亡中的作用和分子机制。采用阿霉素（ADR）诱导建立 HF 小鼠模型。通过 Hoechst 和 TUNEL 染色检测细胞凋亡。通过 qRT-PCR 和 Western blot 检测分子表达。通过 RNA 免疫沉淀（RIP）和 RNA 下拉实验评估 KCNQ1OT1 与融合肉瘤（FUS）之间的相互作用。结果显示，HF 小鼠和 ADR 刺激的小鼠心肌细胞系（HL-1）心肌组织中 KCNQ1OT1 表达上调。KCNQ1OT1 过表达促进 ADR 刺激的 HL-1 细胞凋亡，而 KCNQ1OT1 敲低则产生相反的效果。RIP 和 RNA 下拉结果表明，KCNQ1OT1 与 FUS 结合并负调控其蛋白水平。FUS 敲低抑制 ADR 刺激的 HL-1 细胞凋亡，并逆转 KCNQ1OT1 过表达对心肌细胞凋亡的影响。体内实验表明，KCNQ1OT1 过表达改善心肌组织病理学变化，减少心肌纤维化面积，下调 FUS 表达，抑制 HF 小鼠细胞凋亡。综上所述，KCNQ1OT1 通过靶向 ADR 诱导的 HF 中的 FUS 促进心肌细胞凋亡。
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