Bestrophin 3 ameliorates TNFα-induced inflammation by inhibiting NF-κB activation in endothelial cells

PLoS One. 2014 Oct 20;9(10):e111093. doi: 10.1371/journal.pone.0111093. eCollection 2014.

Abstract

Increasing evidences have suggested vascular endothelial inflammatory processes are the initiator of atherosclerosis. Bestrophin 3 (Best-3) is involved in the regulation of cell proliferation, apoptosis and differentiation of a variety of physiological functions, but its function in cardiovascular system remains unclear. In this study, we investigated the effect of Best-3 on endothelial inflammation. We first demonstrated that Best-3 is expressed in endothelial cells and decreased after tumor necrosis factor-α (TNFα) challenge. Overexpression of Best-3 significantly attenuated TNFα-induced expression of adhesion molecules and chemokines, and subsequently inhibited the adhesion of monocytes to human umbilical vein endothelial cells (HUVECs). Conversely, knockdown of Best-3 with siRNA resulted in an enhancement on TNFα-induced expression of adhesion molecules and chemokines and adhesion of monocytes to HUVECs. Furthermore, overexpression of Best-3 with adenovirus dramatically ameliorated inflammatory response in TNFα-injected mice. Mechanistically, we found up-regulation of Best-3 inhibited TNFα-induced IKKβ and IκBα phosphorylation, IκBα degradation and NF-κB translocation. Our results demonstrated that Best-3 is an endogenous inhibitor of NF-κB signaling pathway in endothelial cells, suggesting that forced Best-3 expression may be a novel approach for the treatment of vascular inflammatory diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bestrophins
  • Cell Adhesion / genetics
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Gene Knockdown Techniques
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Mice
  • Monocytes / metabolism
  • Monocytes / pathology
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Signal Transduction*
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vasculitis / genetics
  • Vasculitis / metabolism
  • Vasculitis / pathology

Substances

  • BEST3 protein, human
  • Bestrophins
  • Chloride Channels
  • Eye Proteins
  • Muscle Proteins
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Vmd2L3 protein, mouse
  • I-kappa B Kinase

Grants and funding

This study was financially supported by the grants from National Natural Scientific Foundation of China (31270992 and 30800215), the project of Zhu Jiang Science and Technology new star of Guangzhou City (2013J2200019), and the Fundamental Research Funds for the Central Universities in Sun Yat-Sen University (13ykpy24). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.