Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute of Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
Department of Cardiology, The Fifth Affiliated Hospital of Xin Jiang Medical University, Urumchi 830001, China.
Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1421-1427. doi: 10.1016/j.bbadis.2019.02.014. Epub 2019 Feb 19.
Pathological cardiac hypertrophy, which may lead to heart failure and sudden death, can be affected by multiple factors. In our previous study, we revealed that IKKi deficiency induced cardiac hypertrophy through the activation of the AKT and NF-kB signaling pathway in response to aortic banding (AB). Non-coding RNAs, mainly long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a crucial role in normal developmental and pathological processes. In the present study, microarray analysis results from GEO database were analyzed, and upregulated lncRNAs in cardiac hypertrophy were identified. Of them, lncRNA cytoskeleton regulator RNA (CYTOR) obtained a fold-change of 6.16 and was positively correlated with IKBKE according to the data from The GTEx project. CYTOR knockdown significantly enhanced the inducible effect of AB operation on mice myocardial hypertrophy and Angiotensin II on cardiomyocyte hypertrophy. Moreover, miR-155 was significantly related to hypertrophic cardiomyopathy (HCM, |hsa05410) and predicted to target both CYTOR and IKBKE. Luciferase reporter and RIP assays revealed that CYTOR served as a ceRNA for miR-155 to counteract miR-155-mediated repression of IKBKE. Moreover, CYTOR knockdown reduced IKKi protein levels while activated NF-kB signaling pathway, whereas miR-155 inhibition exerted an opposing effect; the effect of CYTOR could be partially attenuated by miR-155 inhibition. Taken together, CYTOR might play a protective role in cardiac hypertrophy through miR-155 and downstream IKKi and NF-κB signaling, most possibly through serving as a ceRNA for miR-155 to counteract miR-155-mediated repression of IKBKE.
病理性心肌肥厚可导致心力衰竭和猝死，其发生受多种因素影响。在我们之前的研究中，我们揭示了 IKKi 缺乏通过激活 AKT 和 NF-κB 信号通路，对主动脉缩窄（AB）做出反应，诱导心肌肥厚。非编码 RNA，主要是长非编码 RNA（lncRNA）和 microRNA（miRNA），在正常发育和病理过程中发挥着关键作用。在本研究中，我们对 GEO 数据库中的微阵列分析结果进行了分析，鉴定出心肌肥厚中上调的 lncRNA。其中，lncRNA 细胞骨架调节 RNA（CYTOR）的倍数变化为 6.16，根据 The GTEx 项目的数据，与 IKBKE 呈正相关。在 AB 手术诱导的小鼠心肌肥厚和血管紧张素 II 诱导的心肌细胞肥大中，敲低 CYTOR 显著增强了这种诱导作用。此外，miR-155 与肥厚型心肌病（HCM，|hsa05410）显著相关，并预测靶向 CYTOR 和 IKBKE。荧光素酶报告和 RIP 测定显示，CYTOR 作为 miR-155 的 ceRNA 来拮抗 miR-155 对 IKBKE 的抑制作用。此外，敲低 CYTOR 降低了 IKKi 蛋白水平，同时激活了 NF-κB 信号通路，而抑制 miR-155 则产生相反的效果；miR-155 抑制可部分减弱 CYTOR 的作用。总之，CYTOR 可能通过 miR-155 及其下游的 IKKi 和 NF-κB 信号通路，在心肌肥厚中发挥保护作用，这很可能是通过作为 miR-155 的 ceRNA 来拮抗 miR-155 对 IKBKE 的抑制作用。
