The suppression of bromodomain and extra-terminal domain inhibits vascular inflammation by blocking NF-κB and MAPK activation

Br J Pharmacol. 2017 Jan;174(1):101-115. doi: 10.1111/bph.13657. Epub 2016 Nov 18.


Background and purpose: There is increasing evidence indicating that bromodomain and extra-terminal domain (BET) proteins play a critical role in the regulation of immune and inflammatory responses; however, their contribution to vascular inflammation has not yet been elucidated. In this study, we investigated the effect of inhibiting BET bromodomain on vascular inflammation and the underlying mechanisms.

Experimental approach: HUVECs were isolated from fresh umbilical cords. JQ1, a specific BET bromodomain inhibitor, and Brd shRNA were used to evaluate the regulation of the BET proteins in vascular inflammation. Leukocyte adhesion to HUVECs was measure by an adhesion assay. Western blot or immunohistochemical analysis was used to detect the protein expression. Real-time PCR was used to evaluate mRNA expression. Leukocyte accumulation in vivo was determined by an acute lung inflammation model.

Key results: BET bromodomain inhibition suppressed the expression of adhesion molecules induced by TNF-α- or LPS, including ICAM-1, VCAM-1 and E-selectin, and inhibited leukocyte adhesion to activated HUVEC monolayers. Treatment with JQ1 also attenuated the LPS-induced accumulation of leukocytes and expression of endothelial adhesion molecules in the acute lung inflammation model in vivo. Furthermore, BET bromodomain inhibition reduced the activity of p38 and JNK MAPKs and NF-κB in TNF-α-stimulated HUVECs. TNF-α-induced NF-κB activation was also blocked by inhibitors of p38 (SB203580) or JNK (SP600125).

Conclusions and implications: BET bromodomain is important for regulating endothelial inflammation. Strategies targeting endothelial BET bromodomain may provide a new therapeutic approach for controlling inflammatory-related diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azepines / pharmacology*
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / metabolism*
  • Triazoles / pharmacology*


  • (+)-JQ1 compound
  • Azepines
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Transcription Factors
  • Triazoles
  • Mitogen-Activated Protein Kinases