Chronic vascular inflammation plays a key role in the pathogenesis of atherosclerosis. Long non‐coding RNAs (lncRNAs) have emerged as essential inflammation regulators. We identify a novel lncRNA termed lncRNA‐MAP3K4 that is enriched in the vessel wall and regulates vascular inflammation. In the aortic intima, lncRNA‐MAP3K4 expression was reduced by 50% during the progression of atherosclerosis (chronic inflammation) and 70% during endotoxemia (acute inflammation). lncRNA‐MAP3K4 knockdown reduced the expression of key inflammatory factors (eg, ICAM‐1, E‐selectin, MCP‐1) in endothelial cells or vascular smooth muscle cells and decreased monocytes adhesion to endothelium, as well as reducing TNF‐α, IL‐1β, COX2 expression in macrophages. Mechanistically, lncRNA‐MAP3K4 regulates inflammation through the p38 MAPK signaling pathway. lncRNA‐MAP3K4 shares a bidirectional promoter with MAP3K4, an upstream regulator of the MAPK signaling pathway, and regulates its transcription in cis. lncRNA‐MAP3K4 and MAP3K4 show coordinated expression in response to inflammation in vivo and in vitro. Similar to lncRNA‐MAP3K4, MAP3K4 knockdown reduced the expression of inflammatory factors in several different vascular cells. Furthermore, lncRNA‐MAP3K4 and MAP3K4 knockdown showed cooperativity in reducing inflammation in endothelial cells. Collectively, these findings unveil the role of a novel lncRNA in vascular inflammation by cis‐regulating MAP3K4 via a p38 MAPK pathway.

中文翻译：

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LncRNA-MAP3K4通过p38 MAPK信号通路和MAP3K4的顺式调节调节血管炎症

慢性血管炎症在动脉粥样硬化的发病机制中起关键作用。长链非编码 RNA (lncRNA) 已成为必不可少的炎症调节剂。我们鉴定了一种称为 lncRNA-MAP3K4 的新型 lncRNA，它富含血管壁并调节血管炎症。在主动脉内膜中，lncRNA-MAP3K4 表达在动脉粥样硬化（慢性炎症）进展期间降低 50%，在内毒素血症（急性炎症）期间降低 70%。lncRNA-MAP3K4 敲低降低了内皮细胞或血管平滑肌细胞中关键炎症因子（如 ICAM-1、E-选择素、MCP-1）的表达，减少了单核细胞对内皮的粘附，并降低了 TNF-α、IL ‐1β，巨噬细胞中的 COX2 表达。从机制上讲，lncRNA-MAP3K4 通过 p38 MAPK 信号通路调节炎症。lncRNA-MAP3K4 与 MAP3K4 共享一个双向启动子，MAP3K4 是 MAPK 信号通路的上游调节因子，并顺式调节其转录。lncRNA-MAP3K4 和 MAP3K4 在体内和体外显示出响应炎症的协调表达。与 lncRNA-MAP3K4 类似，MAP3K4 敲低降低了几种不同血管细胞中炎症因子的表达。此外，lncRNA-MAP3K4 和 MAP3K4 敲低在减少内皮细胞炎症方面显示出协同作用。总的来说，这些发现揭示了一种新型 lncRNA 通过 p38 MAPK 通路顺式调节 MAP3K4 在血管炎症中的作用。lncRNA-MAP3K4 和 MAP3K4 在体内和体外显示出响应炎症的协调表达。与 lncRNA-MAP3K4 类似，MAP3K4 敲低降低了几种不同血管细胞中炎症因子的表达。此外，lncRNA-MAP3K4 和 MAP3K4 敲低在减少内皮细胞炎症方面显示出协同作用。总的来说，这些发现揭示了一种新型 lncRNA 通过 p38 MAPK 通路顺式调节 MAP3K4 在血管炎症中的作用。lncRNA-MAP3K4 和 MAP3K4 在体内和体外显示出响应炎症的协调表达。与 lncRNA-MAP3K4 类似，MAP3K4 敲低降低了几种不同血管细胞中炎症因子的表达。此外，lncRNA-MAP3K4 和 MAP3K4 敲低在减少内皮细胞炎症方面显示出协同作用。总的来说，这些发现揭示了一种新型 lncRNA 通过 p38 MAPK 通路顺式调节 MAP3K4 在血管炎症中的作用。