Abstract
AimsEndothelial 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 ResultsWe 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.ConclusionsThese 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.
Highlights
Atherosclerosis remains one of the most important and common causes of death and disability in developed countries [1, 2]
We have shown that human vascular endothelial cell permeability is increased, while transendothelial electrical resistance and VE-cadherin expression were reduced by High-mobility group box 1 protein (HMGB1) treatment
Two store-operated Ca2+ entry (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
Summary
Atherosclerosis remains one of the most important and common causes of death and disability in developed countries [1, 2]. It has been predicted that atherosclerosis will be the main cause of mortality and disability in the world by 2020 [3]. High-mobility group box 1 protein (HMGB1) has been reported to act as a pro-inflammatory factor mediating chronic inflammatory responses in endothelial cells, which in turn play a critical role in atherosclerosis[7,8,9]. Evidence has shown that HMGB1 increases the hyperpermeability of endothelial cells in sepsis and acute lung inflammation [13, 14]. The precise mechanisms by which HMGB1 regulates endothelial hyperpermeability in atherosclerosis remain to be established
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