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

FASEB J. 2021 Jan;35(1):e21133. doi: 10.1096/fj.202001654RR. Epub 2020 Nov 12.


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.

Keywords: ChIP-seq; atherosclerosis; bidirectional promoter; eRNA; vascular cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation*
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • MAP Kinase Kinase Kinase 4 / genetics
  • MAP Kinase Kinase Kinase 4 / metabolism*
  • MAP Kinase Signaling System*
  • Mice
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • Vasculitis / genetics
  • Vasculitis / metabolism*
  • Vasculitis / pathology
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • RNA, Long Noncoding
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 4
  • Map3k4 protein, mouse