Abstract
S100A8, S100A9 and S100A8/A9 complexes have been known as important endogenous damage-associated molecular pattern (DAMP) proteins. But the pathophysiological roles of S100A8, S100A9 and S100A8/A9 in cardiovascular diseases are incompletely explained. In this present study, the effects of homo S100A8, S100A9 and their hetero-complex S100A8/A9 on endothelial barrier function were tested respectively in cultured human umbilical venous endothelial cells (HUVECs). The involvement of TLR4 and RAGE were observed by using inhibitor of TLR4 and blocking antibody of RAGE. The clarification of different MAPK subtypes in S100A8/A9-induced endothelial response was implemented by using specific inhibitors. The calcium-dependency was detected in the absence of Ca2+ or in the presence of gradient-dose Ca2+. The results showed that S100A8, S100A9 and S100A8/A9 could induce F-actin and ZO-1 disorganization in HUVECs and evoked the increases of HUVEC monolayer permeability in a dose- and time-dependent manner. The effects of S100A8, S100A9 and S100A8/A9 on endothelial barrier function depended on the activation of p38 and ERK1/2 signal pathways through receptors TLR4 and RAGE. Most importantly, we revealed the preference of S100A8 on TLR4 and S100A9 on RAGE in HUVECs. The results also showed the calcium dependency in S100A8- and S100A9-evoked endothelial response, indicating that calcium dependency on formation of S100A8 or A9 dimmers might be the prerequisite for this endothelial functional alteration.
Highlights
The calcium-binding proteins S100A8 and S100A9 are pivotal mediators of inflammatory and protective anti-infection responses for the mammalian host [1,2,3,4]
The influence of S100A8, S100A9 or S100A8/A9 on human umbilical venous endothelial cells (HUVECs) monolayer permeability was examined by detecting the Transendothelial electrical resistance (TER) of EC monolayer
Their report shows that S100A8/A9 induce a thrombogenic, inflammatory response in human microvascular endothelial cells by increasing the transcription of proinflammatory chemokines IL-8 and CXCL1, and adhesion molecules VCAM-1 and ICAM-1, and by decreasing the expression of intercellular junction protein cadherin. They further demonstrated that the long term impairment of endothelial integrity induced by HUVECs were stimulated with S100A8 (2.0 mg/mL) (A), S100A9 (2.0 mg/mL) (B) or S100A8/A9 (2.0 mg/mL) (C) for 120 min, with or without 60 min preincubated with SB203580, PD98059 and SP600125 which were used as standard inhibitor for p38, ERK1/2 and JNK, respectively
Summary
The calcium-binding proteins S100A8 and S100A9 are pivotal mediators of inflammatory and protective anti-infection responses for the mammalian host [1,2,3,4]. S100A8 and S100A9 form S100A8/A9 heterodimers (calprotectin) and these proteins and complex have been identified as important endogenous damageassociated molecular pattern (DAMP) proteins. S100A8 or S100A9 shows two calcium-binding sites (EF hands) per protein chain, one of high and one of low affinity for Ca2+ ions. The purified fraction of the S100A8/A9 was found to contain monomers and dimmers. S100A8 and S100A9 are known to form dimmers with themselves, and to form noncovalently linked protein complexes with each other in a Ca2+-dependent manner [5,6]. The S100A8/A9 complex assembly is a Ca2+-regulated process
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