Long non-coding RNA Linc00092 inhibits cardiac fibroblast activation by altering glycolysis in an ERK-dependent manner
Long non-coding RNA Linc00092 inhibits cardiac fibroblast activation by altering glycolysis in an ERK-dependent manner
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长非编码 RNA Linc00092 通过以 ERK 依赖性方式改变糖酵解来抑制心脏成纤维细胞活化
DOI：
10.1016/j.cellsig.2020.109708
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发表时间：
2020-10-01
影响因子：
4.8
通讯作者：
Chen, Yang-Xin
中科院分区：
文献类型：
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作者：
Chen, Zhi-Teng;Zhang, Hai-Feng;Chen, Yang-Xin
目的：心肌成纤维细胞（CF）活化是心肌纤维化的关键事件。糖酵解和糖酵解相关lncrna在CF激活中的作用尚不清楚。因此，我们的目的是研究糖酵解在CF激活中的作用，并确定糖酵解相关的lncrna。主要方法：搜索糖酵解相关lncrna，并在活化的人CF （HCF）和衰竭的人心脏组织中验证其表达谱。调控靶lncRNA的表达，以确定其对HCF激活和糖酵解的影响。lncrna依赖性糖酵解调控的潜在机制也得到了解决。关键发现：转化生长因子- β 1诱导的HCF激活伴随着糖酵解的增强，而2-脱氧- d -葡萄糖（一种特异性糖酵解抑制剂）显著减弱HCF激活。共鉴定出28个糖酵解相关lncrna，其中Linc00092的表达在HCF激活后主要发生变化。在人类心脏组织中，Linc00092主要在心脏成纤维细胞中表达。Linc00092敲低激活hcf，糖酵解增强，而其过表达挽救了hcf的活化表型，糖酵解下调。糖酵解的恢复消除了Linc00092的抗纤维化作用。在活化的hcf中，Linc00092抑制ERK的激活，而在Linc00092敲除的hcf中，ERK抑制抵消了纤维化表型。意义：这些结果表明Linc00092可以通过抑制糖酵解来减弱HCF的激活。Linc00092对ERK的抑制可能在这一过程中起重要作用。总之，这提供了对CF激活机制的更好理解，并可能作为心脏纤维化治疗的新靶点。
Aims: Cardiac fibroblast (CF) activation is the key event for cardiac fibrosis. The role of glycolysis and the glycolysis-related lncRNAs in CF activation are unknown. Thus, we aimed to investigate the role of glycolysis in CF activation and to identify the glycolysis-related lncRNAs involved.Main methods: Glycolysis-related lncRNAs were searched and their expression profiles were validated in activated human CF (HCF) and human failing heart tissues. Expression of the target lncRNA was manipulated to determine its effects on HCF activation and glycolysis. The underlying mechanisms of lncRNA-dependent glycolysis regulation were also addressed.Key findings: HCF activation induced by transforming growth factor-beta 1 was accompanied by an enhanced glycolysis, and 2-Deoxy-D-glucose, a specific glycolysis inhibitor, dramatically attenuated HCF activation. Twenty-eight glycolysis-related lncRNAs were identified and Linc00092 expression was changed mostly upon HCF activation. In human heart tissue, Linc00092 is primarily expressed in cardiac fibroblasts. Linc00092 knockdown activated HCFs with enhanced glycolysis, while its overexpression rescued the activated phenotype of HCFs and down-regulated glycolysis. Restoration of glycolysis abolished the anti-fibrotic effects conferred by Linc00092. Linc00092 inhibited ERK activation in activated HCFs, and ERK inhibition counteracted the fibrotic phenotype in Linc00092 knockdown HCFs.Significance: These results revealed that Linc00092 could attenuate HCF activation by suppressing glycolysis. The inhibition of ERK by Linc00092 may play an important role in this process. Together, this provides a better understanding of the mechanism of CF activation and may serve as a novel target for cardiac fibrosis treatment.