MicroRNA-200a 通过靶向 Keap1/Nrf2 和 β-catenin 通路抑制心肌梗死相关细胞死亡和炎症。
MicroRNA-200a represses myocardial infarction-related cell death and inflammation by targeting the Keap1/Nrf2 and β-catenin pathways.
机构信息
Department of Radiology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, 213164, China.
出版信息
Hellenic J Cardiol. 2021 Mar-Apr;62(2):139-148. doi: 10.1016/j.hjc.2020.10.006. Epub 2020 Nov 13.
BACKGROUND
Acute myocardial infarction (MI) is a main cause of emergency death in the world. MicroRNAs (miRs/miRNAs) are a series of small non-coding RNA molecules, which regulate cardiovascular disorders that involve MI. In this study, we explored the function of miR-200a in MI treatment.
METHODS
We observed down-regulation of miR-200a levels and up-regulation of Keap1 and β-catenin levels in HO-treated newborn murine ventricular cardiomyocytes (NMVCs) and the infarcted heart tissues of MI mouse models, compared to the non-treated NMVCs and normal heart tissues of healthy mice.
RESULTS
CCK-8 and colony formation assays indicated the reduction in NMVC vitality due to HO treatment and the recovery of cell vitality due to miR-200a overexpression, respectively. Flow cytometry with Annexin and PI staining indicated the inhibition of HO-triggered cell apoptosis through ectopically expressed miR-200a. Western blotting and ELISA analyses that detected pro-inflammatory cell factors [interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α] confirmed that miR-200a prevented HO-induced NMVC inflammation. Moreover, miR-200a inhibited up-regulation of Keap1 and β-catenin expression in HO-treated NMVCs by directly binding with the 3'-UTR regions of both Keap1 and β-catenin. Furthermore, overexpression of Keap1 and β-cateninin in HO-treated NMVCs with recovered miR-200a elevated inflammation and apoptosis, respectively.
CONCLUSION
The results showed that miR-200a expression was inhibited in murine cardiomyocytes due to HO stress in MI cardiac tissues and overexpressed miR-200a could protect the cells from death by regulating the Keap1/Nrf2 and β-catenin signal transduction pathways.
背景
急性心肌梗死（MI）是世界范围内导致急诊死亡的主要原因。microRNAs（miRs/miRNAs）是一系列小的非编码 RNA 分子，可调节涉及 MI 的心血管疾病。在这项研究中，我们探讨了 miR-200a 在 MI 治疗中的作用。
方法
与未经处理的 NMVC 和健康小鼠的正常心脏组织相比，我们观察到 HO 处理的新生鼠心室心肌细胞（NMVC）和 MI 小鼠模型的梗死心脏组织中 miR-200a 水平下调，而 Keap1 和 β-连环蛋白水平上调。
结果
CCK-8 和集落形成测定表明，HO 处理导致 NMVC 活力降低，而过表达 miR-200a 则恢复细胞活力。用 Annexin 和 PI 染色的流式细胞术表明，通过异位表达 miR-200a 抑制 HO 触发的细胞凋亡。Western blot 和 ELISA 分析检测促炎细胞因子[白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子（TNF）-α]证实，miR-200a 可预防 HO 诱导的 NMVC 炎症。此外，miR-200a 通过直接结合 Keap1 和 β-连环蛋白的 3'-UTR 区域抑制 HO 处理的 NMVC 中 Keap1 和 β-连环蛋白表达的上调。此外，HO 处理的 NMVC 中 Keap1 和 β-连环蛋白的过表达，在恢复 miR-200a 后分别升高了炎症和细胞凋亡。
结论
结果表明，在 MI 心脏组织中由于 HO 应激，鼠心肌细胞中 miR-200a 的表达受到抑制，而过表达 miR-200a 可以通过调节 Keap1/Nrf2 和 β-连环蛋白信号转导通路来保护细胞免于死亡。
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