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Selenium suppresses oxidative-stress-enhanced vascular smooth muscle cell calcification by inhibiting the activation of the PI3K/AKT and ERK signaling pathways and endoplasmic reticulum stress

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Abstract

Vascular calcification is a prominent feature of many diseases, including atherosclerosis, and it has emerged as a powerful predictor of cardiovascular morbidity and mortality. A number of studies have examined the association between selenium and risk of cardiovascular diseases, but little is known about the role of selenium in vascular calcification. To determine the role of selenium in regulating vascular calcification, we assessed the effect of sodium selenite on oxidative-stress-enhanced vascular smooth muscle cell (VSMC) calcification and the underlying mechanism. Oxidative stress induced by xanthine/xanthine oxidase increased apoptosis, as determined by Hoechst 33342 staining and annexin V/propidium iodide staining, and it enhanced osteoblastic differentiation and calcification of VSMCs, on the basis of alkaline phosphatase activity, the expression of Runx2 and type I collagen, and calcium deposition. These effects of oxidative stress were significantly inhibited by selenite. The following processes may explain the inhibitory effects of selenite: (1) selenite significantly suppressed oxidative stress, as evidenced by the decrease of the oxidative status of the cell and lipid peroxidation levels, as well as by the increase of the total protein thiol content and the activity of the antioxidant selenoenzyme glutathione peroxidase; (2) selenite significantly attenuated oxidative-stress-induced activation of the phosphatidylinositol 3-kinase/AKT and extracellular-signal-regulated kinase signaling pathways, resulting in decreased osteoblastic differentiation of VSMCs; (3) selenite significantly inhibited oxidative-stress-activated endoplasmic reticulum stress, thereby leading to decreased apoptosis. Our results suggest a potential role of selenium in the prevention of vascular calcification, which may provide more mechanistic insights into the relationship between selenium and cardiovascular diseases.

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Abbreviations

ALP:

Alkaline phosphatase

CHOP:

C/EBP homologous protein

Col I:

Type I collagen

2,7-DCFH-DA:

2,7-Dichlorofluorescein diacetate

ER:

Endoplasmic reticulum

ERK:

Extracellular-signal-regulated kinase

FITC:

Fluorescein isothiocyanate

GPx:

Glutathione peroxidase

GRP78:

78-kDa glucose-regulated protein

GSH:

Glutathione

MDA:

Malondialdehyde

MEK1:

Mitogen-activated protein kinase kinase

MTT:

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

PERK:

Protein kinase RNA like ER kinase

PI:

Propidium iodide

PI3K:

Phosphatidylinositol 3-kinase

p-PERK:

Phosphorylated protein kinase RNA like endoplasmic reticulum kinase

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TBS-T:

20 mM tris(hydroxymethyl)aminomethane–HCl, pH 7.5, containing 137 mM NaCl and 0.1 % Tween 20

VSMC:

Vascular smooth muscle cell

XO:

Xanthine oxidase

XXO:

Xanthine/xanthine oxidase

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Acknowledgments

We thank the faculty of the Analytical and Testing Center of Huazhong University of Science and Technology. This work was supported by the National Natural Science Foundation of China (grants 31170775 and 30700136).

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Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, People’s Republic of China

    Hongmei Liu, Xiaoming Li, Fei Qin & Kaixun Huang

  2. Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, Wuhan, 430074, People’s Republic of China

    Hongmei Liu & Kaixun Huang

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  1. Hongmei Liu
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Correspondence to Hongmei Liu.

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Liu, H., Li, X., Qin, F. et al. Selenium suppresses oxidative-stress-enhanced vascular smooth muscle cell calcification by inhibiting the activation of the PI3K/AKT and ERK signaling pathways and endoplasmic reticulum stress. J Biol Inorg Chem 19, 375–388 (2014). https://doi.org/10.1007/s00775-013-1078-1

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