Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, PR China; Laboratory of Cardiac Electrophysiology and Arrhythmia in Guangdong Province, Guangzhou, Guangdong 510120, PR China.
Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, PR China.
Cell Signal. 2020 Oct;74:109708. doi: 10.1016/j.cellsig.2020.109708. Epub 2020 Jul 9.
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.
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.
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.
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.
心肌成纤维细胞（CF）的激活是心肌纤维化的关键事件。糖酵解及其相关长链非编码 RNA（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，并确定涉及的糖酵解相关 lncRNA。
搜索糖酵解相关 lncRNA，并在激活的人 CF（HCF）和人衰竭心脏组织中验证其表达谱。操纵靶标 lncRNA 的表达，以确定其对 HCF 激活和糖酵解的影响。还解决了 lncRNA 依赖性糖酵解调节的潜在机制。
转化生长因子-β1 诱导的 HCF 激活伴随着增强的糖酵解，而 2-脱氧-D-葡萄糖，一种特异性糖酵解抑制剂，可显著减弱 HCF 激活。鉴定出 28 种糖酵解相关 lncRNA，其中 Linc00092 的表达在 HCF 激活时变化最大。在人心脏组织中，Linc00092 主要在心肌成纤维细胞中表达。Linc00092 敲低可激活 HCFs 并增强糖酵解，而其过表达可挽救 HCFs 的激活表型并下调糖酵解。恢复糖酵解可消除 Linc00092 赋予的抗纤维化作用。Linc00092 抑制激活的 HCF 中的 ERK 激活，而 ERK 抑制可拮抗 Linc00092 敲低的 HCF 中的纤维化表型。
这些结果表明，Linc00092 通过抑制糖酵解来减轻 HCF 激活。Linc00092 通过 ERK 的抑制可能在这个过程中发挥重要作用。总之，这提供了对 CF 激活机制的更好理解，并可能成为心脏纤维化治疗的新靶点。
