Abstract
Factors promoting thrombosis such as von Willebrand factor (vWF) and P-selectin are essential for the development of atherosclerosis (AS) and arterial thrombosis. The processing, maturation and release of vWF are regulated by autophagy of vascular endothelial cells. The Sirt1/FoxO1 pathway is an important pathway to regulate autophagy of endothelial cells, therefore the Sirt1/FoxO1 pathway may be an important target for the prevention of thrombosis. We investigated the role of ox-LDL in the release of vWF and P-selectin and the expression of Sirt1 and FoxO1 by Western Blot, Flow Cytometry, ELISA, and tandem fluorescent mRFP-GFP-LC3. We found that vWF and P-selectin secretion increased and Sirt1/FoxO1 pathway was depressed in human umbilical vein endothelial cells (HUVEC) when treated with ox-LDL. Moreover, the expression of autophagy-related protein LC3-II/I and p62 increased. Then, we explored the relationship between autophagy regulated by the Sirt1/FoxO1 pathway and the secretion of vWF and P-selectin. We found that Sirt1/FoxO1, activated by the Sirt1 activators resveratrol (RSV) and SRT1720, decreased the secretion of vWF and P-selectin, which can be abolished by the autophagy inhibitor 3-MA. The expression of Rab7 increased when Sirt1/FoxO1 pathway was activated, and the accumulation of p62 was decreased. Autophagy flux was inhibited by ox-LDL and Sirt1/FoxO1 pathway might enhance autophagy flux through the promotion of the Rab7 expression. Taken together, our data suggest that by enhancing autophagy flux and decreasing the release of vWF and P-selectin, the Sirt1/FoxO1 pathway may be a promising target to prevent AS and arterial thrombosis.
Highlights
Thrombosis, one of the important causes of death in patients with cardiovascular diseases, seriously threatens the life and health of people [1]
Considering that factors promoting thrombosis such as von Willebrand factor (vWF) and P-selectin secreted by endothelial cells are associated with AS, and the processing and maturation and release of vWF is regulated by autophagy, the aim of this study was to explore the function of Oxidized low-density lipoprotein (ox-LDL) on the release of vWF and P-selectin from human umbilical vein endothelial cells (HUVEC), and to assess the effect of autophagy regulated by the Sirt1/FoxO1 pathway on this process
The present study suggests that ox-LDL increased the secretion of vWF and P-selectin from HUVEC, which was related to the effect of ox-LDL on depressing the Sirt1/FoxO1 pathway and autophagy flux in HUVEC
Summary
Thrombosis, one of the important causes of death in patients with cardiovascular diseases, seriously threatens the life and health of people [1]. Factors promoting thrombosis such as von Willebrand factor (vWF) and P-selectin which are stored in Weibel-Palade bodies (WPBs) of endothelial cells play important roles in the development of thrombosis as well as atherosclerosis (AS). VWF is the most abundant protein of WPBs, the processing, maturation and release of which are regulated by autophagy [2]. Recent studies have found that autophagy of endothelial cells is associated with the occurrence and development of cardiovascular diseases. Deficiency in endothelial autophagy induces endothelial apoptosis, endothelial inflammation, and promotes atherosclerotic plaque development [9]
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