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Long non-coding RNA NORAD aggravates acute myocardial infarction by promoting fibrosis and apoptosis via miR-577/COBLL1 axis
Environmental Toxicology ( IF 4.4 ) Pub Date : 2021-08-06 , DOI: 10.1002/tox.23339
Xiaojv Xiong 1 , Jinhua Liu 1 , Qin He 1 , Rui Dai 1 , Hui Zhang 1 , Zhe Cao 1 , Yuanxi Liao 1 , Bo Liu 1 , Yi Zhou 1 , Juan Chen 1 , Jijun Liu 1 , Manhua Chen 1
Affiliation  

Acute myocardial infarction (AMI) is one of the most common and serious cardiovascular diseases. With high morbidity and mortality, AMI has attracted the most attention. Emerging studies indicated that long noncoding RNAs (lncRNAs) play an important role in the progression of AMI. However, the role of NORAD in AMI remained unclear. The current study aimed to investigate the function and mechanism of NORAD in AMI. Bioinformatics tools and a wide range of assays including RT-qPCR, flow cytometry, TTC staining, western blot, luciferase reporter and caspase-3 activity assays were conducted to investigate the function and mechanism of NORAD in AMI. We found out that NORAD was significantly upregulated in AMI rats. Knockdown of NORAD alleviated H9c2 cell injury by reducing apoptosis and decreasing expression levels of fibrogenic factors. In addition, NORAD inhibition ameliorated AMI in a rat model by decreasing infarct size and fibrosis. We confirmed that NORAD bound to miR-577, which was downregulated in ischemia-reperfusion (I/R) rats and hypoxia-exposed H9c2 cells. Additionally, miR-577 combined with the 3′UTR of COBLL1, which was upregulated in I/R rats and hypoxia-exposed H9c2 cells. At last, rescue assay validated that the suppressive effects of NORAD knockdown on apoptosis and expression levels of fibrogenic factors were counteracted by COBLL1 overexpression. Overall, NORAD aggravates acute myocardial infarction by promoting fibrosis and apoptosis via the miR-577/COBLL1 axis. This novel discovery suggested that NORAD may serve as a potential therapeutic target for AMI patients.

中文翻译:

长链非编码RNA NORAD通过miR-577/COBLL1轴促进纤维化和凋亡加重急性心肌梗死

急性心肌梗死(AMI)是最常见和最严重的心血管疾病之一。AMI 的发病率和死亡率都很高,因此备受关注。新兴研究表明,长链非编码 RNA (lncRNAs) 在 AMI 的进展中起重要作用。然而,NORAD 在 AMI 中的作用仍不清楚。本研究旨在探讨 NORAD 在 AMI 中的功能和机制。进行了生物信息学工具和广泛的检测,包括 RT-qPCR、流式细胞术、TTC 染色、蛋白质印迹、荧光素酶报告基因和 caspase-3 活性检测,以研究 NORAD 在 AMI 中的功能和机制。我们发现 NORAD 在 AMI 大鼠中显着上调。敲除 NORAD 通过减少细胞凋亡和降低纤维化因子的表达水平来减轻 H9c2 细胞损伤。此外,NORAD 抑制通过减少梗死面积和纤维化改善了大鼠模型中的 AMI。我们证实 NORAD 与 miR-577 结合,后者在缺血再灌注 (I/R) 大鼠和缺氧暴露的 H9c2 细胞中下调。此外,miR-577 与 COBLL1 的 3'UTR 结合,在 I/R 大鼠和缺氧暴露的 H9c2 细胞中上调。最后,救援实验验证了 NORAD 敲低对细胞凋亡和纤维化因子表达水平的抑制作用被 COBLL1 过表达所抵消。总体而言,NORAD 通过 miR-577/COBLL1 轴促进纤维化和细胞凋亡,从而加重急性心肌梗死。这一新发现表明 NORAD 可以作为 AMI 患者的潜在治疗靶点。我们证实 NORAD 与 miR-577 结合,后者在缺血再灌注 (I/R) 大鼠和缺氧暴露的 H9c2 细胞中下调。此外,miR-577 与 COBLL1 的 3'UTR 结合,在 I/R 大鼠和缺氧暴露的 H9c2 细胞中上调。最后,救援试验验证了 NORAD 敲低对细胞凋亡和纤维化因子表达水平的抑制作用被 COBLL1 过表达所抵消。总体而言,NORAD 通过 miR-577/COBLL1 轴促进纤维化和细胞凋亡,从而加重急性心肌梗死。这一新发现表明 NORAD 可以作为 AMI 患者的潜在治疗靶点。我们证实 NORAD 与 miR-577 结合,后者在缺血再灌注 (I/R) 大鼠和缺氧暴露的 H9c2 细胞中下调。此外,miR-577 与 COBLL1 的 3'UTR 结合,在 I/R 大鼠和缺氧暴露的 H9c2 细胞中上调。最后,救援实验验证了 NORAD 敲低对细胞凋亡和纤维化因子表达水平的抑制作用被 COBLL1 过表达所抵消。总体而言,NORAD 通过 miR-577/COBLL1 轴促进纤维化和细胞凋亡,从而加重急性心肌梗死。这一新发现表明 NORAD 可以作为 AMI 患者的潜在治疗靶点。在 I/R 大鼠和缺氧暴露的 H9c2 细胞中上调。最后,救援实验验证了 NORAD 敲低对细胞凋亡和纤维化因子表达水平的抑制作用被 COBLL1 过表达所抵消。总体而言,NORAD 通过 miR-577/COBLL1 轴促进纤维化和细胞凋亡,从而加重急性心肌梗死。这一新发现表明 NORAD 可以作为 AMI 患者的潜在治疗靶点。在 I/R 大鼠和缺氧暴露的 H9c2 细胞中上调。最后,救援试验验证了 NORAD 敲低对细胞凋亡和纤维化因子表达水平的抑制作用被 COBLL1 过表达所抵消。总体而言,NORAD 通过 miR-577/COBLL1 轴促进纤维化和细胞凋亡,从而加重急性心肌梗死。这一新发现表明 NORAD 可以作为 AMI 患者的潜在治疗靶点。
更新日期:2021-10-01
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