Effect of Autophagy Regulated by Sirt1/FoxO1 Pathway on the Release of Factors Promoting Thrombosis from Vascular Endothelial Cells

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.

Liraglutide protects palmitate-induced INS-1 cell injury by enhancing autophagy mediated via FoxO1

“…However, in the present study, the autophagy inhibitor CQ did not affect the expression of p-FoxO1 in INS-1 cells. The current results were consistent with previously reported findings that the effect of autophagy can be regulated by FoxO1 but the autophagy inhibitor 3-methyadenine had no effect on FoxO1 in vascular endothelial cells ( 19 ). These results indicated that FoxO1 improved the viability of INS-1 cells against PA by upregulating the expression of autophagy-associated proteins.…”

“…In db/db mouse model, FoxO1 knockout decreases glucose-responsive insulin secretion ( 18 ). Moreover, FoxO1 regulates autophagic flux in various cell types, such as vascular endothelial cells ( 19 ), human cholangiocarcinoma QBC939 cells ( 15 ) and rat mesangial cells ( 20 ). However, the effect of FoxO1 on autophagy in pancreatic β-cell has not been fully elucidated.…”

Sirt1 Protects Cartilage Against Degradation through FoxO1 Nucleo-cytoplasmic Shuttling and Positive Regulation of Autophagy

“…Except Resveratrol used in this study, the old drug metformin may alleviate oxidative stress and enhances autophagy in diabetic kidney disease via AMPK/SIRT1-FoxO1 pathway [35], and by enhancing autophagy ux and decreasing the release of vWF and P-selectin. The Sirt1/FoxO1 pathway is also a promising target to prevent atherosclerosis (AS) and arterial thrombosis [36]. Similar to aging and mechanical stress-induced chronic in ammatory diseases in kidney and cardiovascular system, our previous reports [19] and current observations suggested that Sirt1 possibly protected against injury-induced OA with aging via SIRT1/FoxO1/autophagy during OA progress.…”

Novel anti-thrombotic mechanisms mediated by Mas receptor as result of balanced activities between the kallikrein/kinin and the renin-angiotensin systems

“…Murine SIRT1 deficiency leads to increased NF-κB acetylation and activation, reduced KLF2 and thrombomodulin protein expression, and elevated fibrin generation in the lung along with reduced expression of tissue factor pathway inhibitor (TFPI) and increased PAI-1 activity. A recent study by Wu et al showed that SIRT1 dependent deacetylation of transcription factor forkhead box protein O1 (FOXO-1) enhances autophagy, therefore reducing oxidized low-density lipoprotein (ox-LDL)-induced endothelial secretion of Von Willebrand factor and P-selectin, two critical proteins for thrombus formation [ 77 ]. In addition, the role of SIRT1 has also been implicated in deep vein thrombosis [ 78 ].…”