Transcription Factor YY1 Ameliorates Liver Ischemia-reperfusion Injury Through Modulating the miR-181a-5p/ESR1/ERBB2 Axis
Transcription Factor YY1 Ameliorates Liver Ischemia-reperfusion Injury Through Modulating the miR-181a-5p/ESR1/ERBB2 Axis
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DOI：
10.1097/tp.0000000000004356
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发表时间：
2022-11
期刊：
影响因子：
6.2
通讯作者：
Kun Wu;Long Ma;Ting Xu;Jun Cao;Cheng-ming Zhou;Xiangyou Yu;Yi Wang;Hao Wen
中科院分区：
文献类型：
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作者：
Kun Wu;Long Ma;Ting Xu;Jun Cao;Cheng-ming Zhou;Xiangyou Yu;Yi Wang;Hao Wen
背景。肝脏缺血/再灌注损伤（I/RI）以炎症行为为特征。了解炎症的机制对制定治疗策略至关重要。在这项研究中，我们阐明了转录因子阴阳1 （YY1）介导的microRNA (miR)-181a-5p/雌激素受体α (ESR1)/表皮生长因子受体2 （ERBB2）轴在肝脏I/RI中的机制见解。方法。首先，我们建立了小鼠肝脏I/RI模型和小鼠肝细胞（AML12）缺氧再灌注（H/R）细胞模型。随后，检测YY1、miR-181a-5p、ESR1在两种模型中的表达。进一步向I/RI小鼠模型注射携带e-YY1的慢病毒，并对H/ r暴露的AML12细胞进行一系列抑制剂、模拟物和shrna，以验证YY1在肝脏I/RI中控制miR-181a-5p和ESR1的机制。结果。在肝I/RI小鼠和H/ r暴露的肝细胞中，miR-181a-5p表达上调，YY1表达下调。此外，YY1过表达可抑制miR-181a-5p的表达，从而抑制H/ r诱导的肝细胞凋亡和炎症。进一步证实ESR1是miR-181a-5p的靶基因，可被miR-181a-5p负调控。miR-181a-5p抑制升高ESR1表达，从而增强ERBB2表达，减少H/ r诱导的肝细胞凋亡和炎症。结论。总之，这些发现强调YY1抑制miR-181a-5p表达，刺激esr1介导的ERBB2活化，从而改善肝脏I/RI。这项研究为肝脏I/RI的新靶点的发展提供了见解。
Background. Liver ischemia/reperfusion injury (I/RI) is characterized by inflammatory actions. Understanding the mechanistic insights underpinning inflammation is critical to developing treatment strategies. In this study, we illustrated the mechanistic insights of transcription factor Yin-Yang 1 (YY1)-mediated microRNA (miR)-181a-5p/estrogen receptor alpha (ESR1)/epidermal growth factor receptor 2 (ERBB2) axis in liver I/RI. Methods. First, we established liver I/RI models in mice and hypoxia-reperfusion (H/R) cell models in mouse hepatocytes (AML12). Subsequently, the expression of YY1, miR-181a-5p, and ESR1 was determined in the 2 models. I/RI mouse models were further injected with lentivirus carrying oe-YY1‚ and H/R-exposed AML12 cells were subjected to a series of inhibitors, mimics, and shRNAs to validate the mechanisms of YY1 in controlling miR-181a-5p and ESR1 in liver I/RI. Results. Upregulated expression of miR-181a-5p and downregulated expression of YY1 were identified in the liver tissues of liver I/RI mice and H/R-exposed hepatocytes. Moreover, overexpression of YY1 inhibited the miR-181a-5p expression and thus repressed the H/R-induced hepatocyte apoptosis and inflammation. ESR1 was further validated as a target gene of miR-181a-5p and could be negatively regulated by miR-181a-5p. miR-181a-5p inhibition elevated ESR1 expression, which consequently enhanced the ERBB2 expression and reduced H/R-induced hepatocyte apoptosis and inflammation. Conclusions. Overall, these findings highlighted that YY1 repressed the miR-181a-5p expression and stimulated ESR1-mediated activation of ERBB2, thereby ameliorating liver I/RI. This study provides insight into the development of novel targets for liver I/RI.