Store-operated Ca2+ entry plays a role in HMGB1-induced vascular endothelial cell hyperpermeability

PLoS One. 2015 Apr 17;10(4):e0123432. doi: 10.1371/journal.pone.0123432. eCollection 2015.

Abstract

Aims: Endothelial dysfunction, including increased endothelial permeability, is considered an early marker for atherosclerosis. High-mobility group box 1 protein (HMGB1) and extracellular Ca2+ entry, primarily mediated through store-operated Ca2+ entry (SOCE), are known to be involved in increasing endothelial permeability. The aim of this study was to clarify how HMGB1 could lead to endothelia hyperpermeability.

Methods and results: We have shown that human vascular endothelial cell permeability is increased, while transendothelial electrical resistance and VE-cadherin expression were reduced by HMGB1 treatment. Two SOCE inhibitors and knockdown of stromal interaction molecule 1 (STIM1), a Ca2+ sensor mediating SOCE, inhibited the HMGB1-induced influx of Ca2+ and Src activation followed by significant suppression of endothelial permeability. Moreover, knockdown of Orai1, an essential pore-subunit of SOCE channels, decreased HMGB1-induced endothelial hyperpermeability.

Conclusions: These data suggest that SOCE, acting via STIM1, might be the predominant mechanism of Ca2+ entry in the modulation of endothelial cell permeability. STIM1 may thus represent a possible new therapeutic target against atherosclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Cadherins / metabolism
  • Calcium / metabolism*
  • Calcium Channels / metabolism
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • HMGB1 Protein / pharmacology*
  • Human Umbilical Vein Endothelial Cells / cytology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Membrane Proteins / metabolism
  • Neoplasm Proteins / metabolism
  • Permeability
  • Stromal Interaction Molecule 1

Substances

  • Cadherins
  • Calcium Channels
  • HMGB1 Protein
  • Membrane Proteins
  • Neoplasm Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Calcium

Grants and funding

This study was supported by National Natural Science Foundation of China (81270087); President Foundation of Nanfang Hospital, Southern Medical University (2013C008,2012C001); Scientific Research Initiative of Southern Medical University (PY2013N027).