LncRNA‐MAP3K4 regulates vascular inflammation through the p38 MAPK signaling pathway and cis ‐modulation of MAP3K4

Abstract 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.