Credit: Kevin MacKenzie
Two preclinical studies provide new insight into the activity of STXBP5, a gene that has been linked to changes in von Willebrand factor (VWF).
One research group found evidence suggesting that STXBP5 regulates endothelial exocytosis and thrombosis.
Another group’s work indicated that STXBP5 is required for normal arterial hemostasis, as it contributes to platelet packaging and secretion.
Both studies appear in The Journal of Clinical Investigation.
Charles Lowenstein, MD, of the University of Rochester in New York, and his colleagues began their research with the theory that STXBP5 inhibits endothelial cell exocytosis.
The group found that STXBP5 is expressed in human endothelial cells, and reducing STXBP5 increases exocytosis of VWF and P-selectin.
STXBP5-knockout mice had higher levels of VWF in their plasma, increased P-selectin translocation, and more platelet-endothelial interactions. This suggests that defective STXBP5 is a risk factor for thrombosis.
However, STXBP5-knockout mice also exhibited prolonged bleeding and impaired thrombosis. They had defects in platelet secretion and activation as well.
Sidney (Wally) Whiteheart, PhD, of the University of Kentucky in Lexington, and his colleagues helped to explain these findings with their research.
The group showed that platelets lacking SXTBP5 failed to function correctly, and SXTBP5 was required for platelets to assist in normal clot formation. This suggests STXBP5 plays different roles in endothelial cells and platelets.
Specifically, the researchers found that STXBP5 interacts with core secretion machinery complexes and the platelet cytoskeleton.
And platelets from STXBP5-knockout mice exhibited defects in granule secretion. These platelets had altered granule cargo levels, despite having normal morphology and granule numbers.
Like Dr Lowenstein’s group, Dr Whiteheart and his colleagues observed dramatic bleeding and defective hemostasis in STXBP5-knockout mice. Transplant experiments suggested these defects were due to a loss of STXBP5 in bone marrow-derived cells.
