Department of Emergency, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
Department of Gastroenterological Surgery, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu, China.
J Cell Physiol. 2020 Jan;235(1):105-113. doi: 10.1002/jcp.28791. Epub 2019 Jul 25.
The biological function of long noncoding RNA NEAT1 has been revealed in a lot of diseases. Nevertheless, it is still not yet clear whether NEAT1 can modulate the process of myocardial ischemia-reperfusion injury (M-I/R). Here, we reported that NEAT1 was able to sponge miR-495-3p to contribute to M-I/R injury through activating mitogen-activated protein kinase 6 (MAPK6). First, elevated expression of NEAT1 was revealed in M-I/R injury mice, meanwhile, lactate dehydrogenase (LDH) and creatine kinase-muscle/brain (CK-MB) were also upregulated in the serum. Meanwhile, as previously reported, miR-495 serves as a tumor suppressor or an oncogenic miRNA in different types of cancer. Currently, we found miR-495-3p was remarkably reduced in M-I/R mice. Additionally, NEAT1 was significantly induced whereas miR-495-3p was greatly reduced by H O treatment in H9C2 cells. Moreover, loss of NEAT1 in H9C2 cells could repress the viability and proliferation of cells. For another, overexpression of NEAT1 exhibited an opposite phenomenon. Furthermore, LDH release and caspase-3 activity were obviously triggered by upregulation of NEAT1 while suppressed by NEAT1 knockdown. miR-495-3p was indicated and validated as a target of NEAT1 using the analysis of bioinformatics. Interestingly, we observed that miR-495-3p mimics repressed tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-18 protein expression while their levels were enhanced by the inhibition of miR-495-3p in H9c2 cells. Subsequently, it was manifested that MAPK6 was a target of miR-495-3p, which could exert a lot in the NEAT1/miR-495-3p-mediated M-I/R injury. Overall, our results implied that NEAT1 contributed to M-I/R injury via the modulation of miR-495-3p and MAPK6.
长链非编码 RNA NEAT1 的生物学功能在许多疾病中已经得到揭示。然而，目前尚不清楚 NEAT1 是否可以调节心肌缺血再灌注损伤（M-I/R）的过程。在这里，我们报道 NEAT1 能够通过激活丝裂原活化蛋白激酶 6（MAPK6）来海绵吸附 miR-495-3p，从而导致 M-I/R 损伤。首先，在 M-I/R 损伤的小鼠中发现 NEAT1 的表达升高，同时血清中的乳酸脱氢酶（LDH）和肌酸激酶-肌肉/脑（CK-MB）也升高。同时，正如之前报道的那样，miR-495 在不同类型的癌症中既可以作为肿瘤抑制因子，也可以作为致癌 miRNA。目前，我们发现 miR-495-3p 在 M-I/R 小鼠中显著减少。此外，在 H9C2 细胞中，H 2 O 2 处理显著诱导 NEAT1，同时显著降低 miR-495-3p 的表达。此外，在 H9C2 细胞中敲低 NEAT1 可以抑制细胞的活力和增殖。另一方面，过表达 NEAT1 则表现出相反的现象。此外，上调 NEAT1 明显触发 LDH 释放和 caspase-3 活性，而敲低 NEAT1 则抑制其释放和活性。通过生物信息学分析表明，miR-495-3p 是 NEAT1 的一个靶标。有趣的是，我们观察到 miR-495-3p 模拟物抑制肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-18 蛋白的表达，而在 H9c2 细胞中抑制 miR-495-3p 则增强其表达。随后，MAPK6 被证明是 miR-495-3p 的靶标，它在 NEAT1/miR-495-3p 介导的 M-I/R 损伤中发挥了重要作用。总的来说，我们的研究结果表明，NEAT1 通过调节 miR-495-3p 和 MAPK6 促进 M-I/R 损伤。
