Affiliation:
1. From the Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (I.B., S.R.P., X.C., P.M.-D., A.R.R.)
2. Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City (A.R.R.).
Abstract
Objective—
Inorganic polyphosphate (polyP) is known to modulate coagulation, inflammation, and metabolic pathways. It also amplifies inflammatory responses of HMGB1 (high mobility group box 1) in endothelial cells. The objective of this study was to evaluate the effect of polyP on von Willebrand factor (VWF) release from endothelial cells with or without HMGB1.
Approach and Results—
EA.hy926 endothelial cells were treated with different concentrations of polyP
70
alone or in combination with different concentrations of HMGB1. VWF release was measured by an ELISA assay in the absence or presence of pharmacological inhibitors of the receptor for advanced glycation end products, P2Y
1
, and Ca
2+
. A flow chamber assay was used to monitor polyP
70
-mediated platelet recruitment and VWF-platelet string formation. PolyP
70
and HMGB1 induced VWF release from endothelial cells by a concentration-dependent manner. PolyP
70
amplified HMGB1-mediated VWF release from endothelial cells. This was also true if boiled platelet releasate was used as the source of polyP. Gene silencing or pharmacological inhibitors of receptor for advanced glycation end products, P2Y
1
, and Ca
2+
significantly inhibited VWF release. PolyP
70
and HMGB1 synergistically promoted VWF-platelet string formation in the flow chamber assay, which was inhibited by the anti-GPIbα (glycoprotein Ib alpha) antibody. VWF release by polyP
70
-HMGB1 complex required phosphorylation of Src and phospholipase C because inhibitors of Src, phospholipase C, and Ca
2+
signaling significantly decreased VWF secretion. The polyP
70
-HMGB1 complex also increased angiopoietin-2 release, indicating that Weibel-Palade body exocytosis is involved in the VWF release.
Conclusions—
PolyP
70
can promote thrombotic and inflammatory pathways by inducing VWF release and platelet string formation on endothelial cells.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
24 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献