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-β1 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.

中文翻译：

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长链非编码 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。

宗旨

心脏成纤维细胞 (CF) 激活是心脏纤维化的关键事件。糖酵解和糖酵解相关的 lncRNA 在 CF 激活中的作用尚不清楚。因此，我们旨在研究糖酵解在 CF 激活中的作用，并确定所涉及的糖酵解相关 lncRNA。

主要方法

搜索了与糖酵解相关的 lncRNA，并在活化的人类 CF (HCF) 和人类衰竭的心脏组织中验证了它们的表达谱。操纵目标 lncRNA 的表达以确定其对 HCF 活化和糖酵解的影响。还讨论了 lncRNA 依赖性糖酵解调节的潜在机制。

主要发现

通过转化生长因子β1诱导HCF激活是伴随着增强的糖酵解，和2-脱氧ð葡萄糖，特定的糖酵解抑制剂，显着地减弱HCF活化。鉴定了 28 种与糖酵解相关的 lncRNA，并且 Linc00092 的表达主要在 HCF 激活时发生变化。在人类心脏组织中，Linc00092 主要在心脏成纤维细胞中表达。Linc00092 敲低激活了具有增强糖酵解的 HCF，而其过表达挽救了 HCF 的活化表型并下调了糖酵解。糖酵解的恢复消除了 Linc00092 赋予的抗纤维化作用。Linc00092 抑制活化 HCF 中的 ERK 活化，并且 ERK 抑制抵消了 Linc00092 敲低 HCF 中的纤维化表型。

意义

这些结果表明，Linc00092 可以通过抑制糖酵解来减弱 HCF 的活化。Linc00092 对 ERK 的抑制可能在此过程中起重要作用。总之，这提供了对 CF 激活机制的更好理解，并可作为心脏纤维化治疗的新靶点。