Journal Article

Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

Lowenstein, Charles J., Zhu, Qiuyu, de la Luz Garcia-Hernandez, Maria, Takai, Yoshimi, LoMonaco, Michael B., Morrell, Craig N., O’Donnell, Christopher J., Yamakuchi, Munekazu, Ko, Kyung Ae, Modjeski, Kristina L., Johnson, Andrew D., Ture, Sara

2014

Overview

In humans, vWF levels predict the risk of myocardial infarction and thrombosis; however, the factors that influence vWF levels are not completely understood. Recent genome-wide association studies (GWAS) have identified syntaxin-binding protein 5 (STXBP5) as a candidate gene linked to changes in vWF plasma levels, though the functional relationship between STXBP5 and vWF is unknown. We hypothesized that STXBP5 inhibits endothelial cell exocytosis. We found that STXBP5 is expressed in human endothelial cells and colocalizes with and interacts with syntaxin 4. In human endothelial cells reduction of STXBP5 increased exocytosis of vWF and P-selectin. Mice lacking Stxbp5 had higher levels of vWF in the plasma, increased P-selectin translocation, and more platelet-endothelial interactions, which suggests that STXBP5 inhibits endothelial exocytosis. However, Stxbp5 KO mice also displayed hemostasis defects, including prolonged tail bleeding times and impaired mesenteric arteriole and carotid artery thrombosis. Furthermore, platelets from Stxbp5 KO mice had defects in platelet secretion and activation; thus, STXBP5 inhibits endothelial exocytosis but promotes platelet secretion. Our study reveals a vascular function for STXBP5, validates the functional relevance of a candidate gene identified by GWAS, and suggests that variation within STXBP5 is a genetic risk for venous thromboembolic disease.

• Publisher: American Society for Clinical Investigation
• Subject: ADAM Proteins - metabolism / ADAMTS13 Protein / Animals / Aorta - metabolism / Binding proteins / Biomedical research / Blood clots / Blood platelets / Blood Platelets - cytology / Chromosomes / Endothelial Cells - cytology / Endothelium - metabolism / Exocytosis / Gene Expression Regulation / Genes / Genetic aspects / Genetic variation / HEK293 Cells / Human Umbilical Vein Endothelial Cells / Humans / Identification and classification / Laboratory animals / Male / Metalloendopeptidases - metabolism / Mice / Mice, Inbred C57BL / Mice, Knockout / Microcirculation / Mortality / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / P-Selectin - metabolism / Plasma / Proteins / Qa-SNARE Proteins - metabolism / R-SNARE Proteins - genetics / R-SNARE Proteins - metabolism / Risk factors / Studies / Thromboembolism / Thrombosis / von Willebrand Factor - metabolism