Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4
Circular RNA circRNA_000203 aggravates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p binding to Gata4
复制标题
环状RNA circRNA_000203通过抑制miR-26b-5p和miR-140-3p与Gata4的结合加剧心脏肥大
DOI：
10.1093/cvr/cvz215
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发表时间：
2020-06-01
影响因子：
10.8
通讯作者：
Shan, Zhi-Xin
中科院分区：
文献类型：
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作者：
Li, Hui;Xu, Jin-Dong;Shan, Zhi-Xin
摘要 目的 环状 RNA (circRNA) 参与多种生理和病理过程中的基因调控。本研究旨在探讨circRNA_000203对心脏肥大的影响及其潜在机制。方法和结果发现 CircRNA_000203 在 Ang-II 输注小鼠的心肌和 Ang-II 处理的新生小鼠心室心肌细胞 (NMVC) 的细胞质中上调。 circRNA_000203 的强制表达可增强 NMVC 中的细胞大小以及心房钠尿肽和 β-肌球蛋白重链的表达。在体内，注入Ang-II的心肌特异性circRNA_000203转基因小鼠（Tg-circ203）的心脏功能受损，心脏肥大加剧。从机制上讲，我们发现 circRNA_000203 可以特异性地海绵 NMVC 中的 miR-26b-5p、-140-3p。此外，双荧光素酶报告基因检测显示miR-26b-5p、-140-3p可以与Gata4基因的3'-UTR相互作用，而circRNA_000203可以阻断上述相互作用。此外，Gata4 表达在 NMVC 中受到 miR-26b-5p、-140-3p 模拟物的转录抑制，但在体外和体内通过 circRNA_000203 的过表达而增强。从功能上讲，miR-26b-5p、-140-3p 和 Gata4 siRNA 可以逆转 Ang-II 诱导的 NMVC 的肥大生长，并消除 circRNA_000203 在 NMVC 中的促肥大作用。此外，我们证明 NF-κB 信号传导介导接受 Ang-II 处理的 NMVC 中 circRNA_000203 的上调。结论 我们的数据表明，circRNA_000203 通过抑制 miR-26b-5p 和 miR-140-3p 导致 Gata4 水平升高，从而加剧心脏肥大。
Abstract Aims Circular RNAs (circRNAs) are involved in gene regulation in a variety of physiological and pathological processes. The present study aimed to investigate the effect of circRNA_000203 on cardiac hypertrophy and the potential mechanisms involved. Methods and results CircRNA_000203 was found to be up-regulated in the myocardium of Ang-II-infused mice and in the cytoplasma of Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Enforced expression of circRNA_000203 enhances cell size and expression of atrial natriuretic peptide and β-myosin heavy chain in NMVCs. In vivo, heart function was impaired and cardiac hypertrophy was aggravated in Ang-II-infused myocardium-specific circRNA_000203 transgenic mice (Tg-circ203). Mechanistically, we found that circRNA_000203 could specifically sponge miR-26b-5p, -140-3p in NMVCs. Further, dual-luciferase reporter assay showed that miR-26b-5p, -140-3p could interact with 3′-UTRs of Gata4 gene, and circRNA_000203 could block the above interactions. In addition, Gata4 expression is transcriptionally inhibited by miR-26b-5p, -140-3p mimic in NMVCs but enhanced by over-expression of circRNA_000203 in vitro and in vivo. Functionally, miR-26b-5p, -140-3p, and Gata4 siRNA, could reverse the hypertrophic growth in Ang-II-induced NMVCs, as well as eliminate the pro-hypertrophic effect of circRNA_000203 in NMVCs. Furthermore, we demonstrated that NF-κB signalling mediates the up-regulation of circRNA_000203 in NMVCs exposed to Ang-II treatment. Conclusions Our data demonstrated that circRNA_000203 exacerbates cardiac hypertrophy via suppressing miR-26b-5p and miR-140-3p leading to enhanced Gata4 levels.