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Selenoprotein S inhibits inflammation-induced vascular smooth muscle cell calcification

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Abstract

Vascular calcification is a prominent feature of many diseases including atherosclerotic cardiovascular disease (CVD), leading to high morbidity and mortality rates. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism is far from clear. To investigate the role of SelS in inflammation-induced vascular calcification, osteoblastic differentiation and calcification of vascular smooth muscle cells (VSMCs) induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α were compared between the cells with and without SelS knockdown. LPS or TNF-α induced osteoblastic differentiation and calcification of VSMCs, as showed by the increases of runt-related transcription factor 2 (Runx2) protein levels, Runx2 and type I collagen mRNA levels, alkaline phosphatase activity, and calcium deposition content. These changes were aggravated when SelS was knocked down by small interfering RNA. Moreover, LPS activated both classical and alternative pathways of nuclear factor-κB (NF-κB) signaling in calcifying VSMCs, which were further enhanced under SelS knockdown condition. SelS knockdown also exacerbated LPS-induced increases of proinflammatory cytokines TNF-α and interleukin-6 expression, as well as increases of endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 and inositol-requiring enzyme 1α expression in calcifying VSMCs. In conclusion, the present study suggested that SelS might inhibit inflammation-induced VSMC calcification probably by suppressing activation of NF-κB signaling pathways and ER stress. Our findings provide new understanding of the role of SelS in vascular calcification, which will be potentially beneficial to the prevention of atherosclerotic CVD.

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Abbreviations

AAS:

Atomic absorption spectroscopy

ALP:

Alkaline phosphatase

BSA:

Bovine serum albumin

Col I:

Type I collagen

CVD:

Cardiovascular disease

DMEM:

Dulbecco modified Eagle’s medium

ECL:

Enhanced chemiluminescence

ER:

Endoplasmic reticulum

ERAD:

ER-associated protein degradation

FCS:

Fetal calf serum

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

GRP78:

78-kDa glucose-regulated protein

IL:

Interleukin

IRE1α:

Inositol-requiring enzyme 1α

LPS:

Lipopolysaccharide

MTT:

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NF-κB:

Nuclear factor-κB

PCR:

Polymerase chain reaction

RANKL:

Receptor activator of NF-κB ligand

ROS:

Reactive oxygen species

Runx2:

Runt-related transcription factor 2

SelS:

Selenoprotein S

siRNA:

Small interference RNA

TNF-α:

Tumor necrosis factor-α

VSMCs:

Vascular smooth muscle cells

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant no. 21771068 and 31170775), the Fundamental Research Funds for the Central Universities of China (grant no. 2017KFYXJJ167) and Excellent Youth Foundation of Hubei Scientific Committee (grant no. 2014CFA022). We thank Analytical and Testing Center of Huazhong University of Science and Technology for allowing us to use its facilities.

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Authors and Affiliations

  1. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, People’s Republic of China

    Yali Ye, Weixia Bian, Fen Fu & Hongmei Liu

  2. Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, 48824, USA

    Jian Hu

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  1. Yali Ye
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  2. Weixia Bian
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  3. Fen Fu
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  4. Jian Hu
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Correspondence to Hongmei Liu.

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Ye, Y., Bian, W., Fu, F. et al. Selenoprotein S inhibits inflammation-induced vascular smooth muscle cell calcification. J Biol Inorg Chem 23, 739–751 (2018). https://doi.org/10.1007/s00775-018-1563-7

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