Constitutive Oxidative Stress by SEPHS1 Deficiency Induces Endothelial Cell Dysfunction.

Jisu Jung,Bradley A Carlson,Byeong Jae Lee,Jiwoon Na,Jeyoung Bang,Dolph L Hatfield,Tack-Jin Yoo,Jin-Hong Kim,Donghyun Kang,Lark Kyun Kim,Lu Qiao,Dongin Kwon,Yoomin Kim

doi:10.3390/ijms222111646

Abstract

The primary function of selenophosphate synthetase (SEPHS) is to catalyze the synthesis of selenophosphate that serves as a selenium donor during selenocysteine synthesis. In eukaryotes, there are two isoforms of SEPHS (SEPHS1 and SEPHS2). Between these two isoforms, only SEPHS2 is known to contain selenophosphate synthesis activity. To examine the function of SEPHS1 in endothelial cells, we introduced targeted null mutations to the gene for SEPHS1, Sephs1, in cultured mouse 2H11 endothelial cells. SEPHS1 deficiency in 2H11 cells resulted in the accumulation of superoxide and lipid peroxide, and reduction in nitric oxide. Superoxide accumulation in Sephs1-knockout 2H11 cells is due to the induction of xanthine oxidase and NADPH oxidase activity, and due to the decrease in superoxide dismutase 1 (SOD1) and 3 (SOD3). Superoxide accumulation in 2H11 cells also led to the inhibition of cell proliferation and angiogenic tube formation. Sephs1-knockout cells were arrested at G2/M phase and showed increased gamma H2AX foci. Angiogenic dysfunction in Sephs1-knockout cells is mediated by a reduction in nitric oxide and an increase in ROS. This study shows for the first time that superoxide was accumulated by SEPHS1 deficiency, leading to cell dysfunction through DNA damage and inhibition of cell proliferation.

Highlights

Selenium is an essential trace element that provides many health benefits
Levels of scavengers of lipid peroxidation products such as addition, we found that mRNA levels of scavengers of lipid peroxidation products such glutaredoxin (Glrx1), peroxiredoxin (Prdx1), glutathione
GADD45β showed a similar pattern to cyclin A2, suggesting G2/M phase arrest occurred through DNA damage (Figure 5E). These results strongly suggest that the superoxide accumulated by Sephs1 knockout resulted in gamma formation through a doublesuperoxide accumulated by Sephs1 knockout resulted in gamma formation through a double-strand break, that this DNA

Summary

Introduction

Selenium is an essential trace element that provides many health benefits. For example, selenium has been shown to prevent heart disease, have antiviral effects, and to boost the immune system, when it is consumed in adequate amounts, as discussed in [1]and references therein. Selenium is an essential trace element that provides many health benefits. Selenium has been shown to prevent heart disease, have antiviral effects, and to boost the immune system, when it is consumed in adequate amounts, as discussed in [1]. This element plays important roles in animal development and in the male reproductive system. Most of the beneficial effects of selenium are likely mediated by selenoproteins, which contain selenocysteine (Sec) at the active site [2]. Selenocysteine, the 21st amino acid in the genetic code, can be incorporated into a growing peptide in response to UGA codon translation [3,4]. Sec is produced by replacing the hydroxyl group of serine that is aminoacylated on tRNA[Ser]Sec with inorganic selenium [2]

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Results

Conclusion