Abstract 11567: STXBP5 Regulates Endothelial Exocytosis, Platelet Secretion and Thrombosis
Introduction: Von Willebrand factor (VWF) levels predict the risk of MI and thrombosis, but the factors influencing 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, but the functional significance of STXBP5 is unknown.
Hypothesis: We hypothesized that STXBP5 regulates endothelial cell exocytosis and thrombosis.
Methods: We knocked down STXBP5 in endothelial cells and measured VWF release changes. We searched for interactions between STXBP5 and proteins that regulates vesicle trafficking. We conducted phenotypic analyses including endothelial exocytosis, platelet function assay, and thrombosis in wild-type and STXBP5 null mice. We performed murine bone marrow transplantation to identify the relative importance of endothelial and platelet STXBP5 in regulating thrombotic phenotypes.
Results: STXBP5 is expressed in human endothelial cells and co-localizes and interacts with syntaxin 4 and synaptotagmin 1. Knockdown of STXBP5 increased endothelial exocytosis of VWF. Mice lacking Stxbp5 have higher plasma VWF level, increased P-selectin translocation, and more platelet-endothelial interactions. These data suggest STXBP5 inhibits endothelial exocytosis. Surprisingly, mice lacking Stxbp5 also display hemostasis defects, with prolonged tail bleeding time, and severely impaired mesenteric arteriole and carotid artery thrombi formation. Moreover, platelets from Stxbp5 null mice have defects in secretion and activation. Therefore, STXBP5 inhibits endothelial exocytosis, but promotes platelet secretion and thrombosis. Finally, plasma VWF level was unchanged by alteration of the bone marrow phenotype, but thrombotic phenotype was transferable with the bone marrow, suggesting STXBP5 in endothelial cells determines plasma VWF level, but STXBP5 in bone marrow-derived cells, presumably platelets, dominates the thrombotic phenotype.
Conclusions: Our study reveals a dual vascular role for STXBP5: STXBP5 inhibits endothelial exocytosis but promotes platelet exocytosis. Our data in combination with prior GWAS suggest that STXBP5 is a novel regulator of venous thromboembolic disease.
Author Disclosures: Q. Zhu: None. M. Yamakuchi: None. S. Ture: None. M. Garcia-Hernandez: None. K. Ko: None. K.L. Modjeski: None. M.B. LoMonaco: None. A.D. Johnson: None. C.J. O’Donnell: None. Y. Takai: None. C.N. Morrell: None. C.J. Lowenstein: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.