Abstract
Endothelial dysfunction, partly induced by inflammatory mediators, is known to initiate and promote several cardiovascular diseases. Selenoprotein S (SelS) has been identified in endothelial cells and is associated with inflammation; however, its function in inflammation-induced endothelial dysfunction has not been described. We first demonstrated that the upregulation of SelS enhances the levels of nitric oxide and endothelial nitric oxide synthase in tumor necrosis factor- (TNF-) α-treated human umbilical vein endothelial cells (HUVECs). The levels of TNF-α-induced endothelin-1 and reactive oxygen species are also reduced by the upregulation of SelS. Furthermore, SelS overexpression blocks the TNF-α-induced adhesion of THP-1 cells to HUVECs and inhibits the increase in intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. Moreover, SelS overexpression regulates TNF-α-induced inflammatory factors including interleukin-1β, interleukin-6, interleukin-8, and monocyte chemotactic protein-1 and attenuates the TNF-α-induced activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways. Conversely, the knockdown of SelS with siRNA results in an enhancement of TNF-α-induced injury in HUVECs. These findings suggest that SelS protects endothelial cells against TNF-α-induced dysfunction by inhibiting the activation of p38 MAPK and NF-κB pathways and implicates it as a possible modulator of vascular inflammatory diseases.
Highlights
The vascular endothelium is regarded as a dynamic organ between blood vessels and circulating blood and plays a crucial role in the cardiovascular system, including the control of fibrinolysis and coagulation, regulation of vascular tone, inflammatory responses and angiogenesis processes, and synthesis and secretion of vasoactive substances [1]
We found that tumor necrosis factor- (TNF-)α increased Selenoprotein S (SelS) expression in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner (Figure 1), indicating that Tumor necrosis factor-α (TNF-α) regulates SelS expression, and suggesting that SelS plays a critical role in endothelial inflammation
We have shown that the upregulation of SelS improves the viability of endothelial cells, enhances the levels of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS), reduces the production of ET-1 and reactive oxygen species (ROS), and inhibits the adhesion of TNF-α-induced THP-1 cells to endothelial cells
Summary
The vascular endothelium is regarded as a dynamic organ between blood vessels and circulating blood and plays a crucial role in the cardiovascular system, including the control of fibrinolysis and coagulation, regulation of vascular tone, inflammatory responses and angiogenesis processes, and synthesis and secretion of vasoactive substances [1]. Vascular equilibrium is regulated by a strict balance between agonist and antagonist substances secreted by the endothelium. NO is a potent relaxing factor that plays a fundamental role in the maintenance of vasomotor function. It inhibits leukocyte adhesion, platelet aggregation, vascular smooth muscle cells (VSMCs) proliferation, and extracellular matrix secretion [2]. Reduced NO and an imbalance between NO and constriction factors such as endothelin-1
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