Abstract 181: VAMP8 Mediates Endothelial Granule Exocytosis
| Autor: | Qiuyu Zhu, Clare Bao, Sara Ture, Marcella Ferlito, Craig N Morrell, Munekazu Yamakuchi, Charles J Lowenstein |
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| Rok vydání: | 2014 |
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| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 34 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Endothelial cells maintain the integrity of the vasculature. In response to injury, endothelial cells undergo exocytosis, releasing various compounds into the blood stream by vesicle fusion with the plasma membrane. Endothelial exocytosis provokes inflammation and thrombosis as one of the earliest responses to vascular injury. Enhanced understanding of these events may lead to novel treatments for vascular diseases such as atherosclerosis, stroke, myocardial infarction, and thrombosis. However, the exocytic machinery that regulates granule secretion from endothelial cells is not completely defined. We tested the hypothesis that specific proteins in the soluble N-ethylmaleimide sensitive factor receptor attachment protein (SNARE) superfamily are associated with the endothelial-specific secretory organelles, Weibel-Palade bodies (WPBs), and mediates endothelial exocytosis. We found that human endothelial cells express members of the SNARE superfamily, including vesicle associated membrane protein 3 (VAMP3), VAMP8, syntaxin 4 (STX4), and synaptosomal associated protein 23 (SNAP23). Out of all these proteins, we found that only VAMP8 co-localizes with WPBs containing von Willebrand Factor (VWF), the major component of endothelial granules. Furthermore, VAMP8 also interacts with STX4, another SNARE component of the exocytic machinery. To explore the role of VAMP8 in regulating endothelial granule exocytosis, we knocked down VAMP8 expression with siRNA in endothelial cells. Decreasing VAMP8 expression impairs exocytosis; conversely, rescue of VAMP8 expression after VAMP8 knockdown restores exocytosis to normal level. Mice lacking VAMP8 have decreased endothelial exocytosis, as measured by decreased plasma VWF levels and decreased leukocyte rolling along vessels. In conclusion, our data suggest that VAMP8 plays a critical role in mediating endothelial exocytosis and may be a potential therapeutic target for vascular inflammatory and thrombotic diseases. |
| Databáze: | OpenAIRE |
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