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Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress

1
Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Nanchang University, Nanchang 330006, Jiangxi, China
2
School of Basic Medical Experiments Center, Nanchang University, Nanchang 330006, Jiangxi, China
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(12), 2861; https://doi.org/10.3390/ijms20122861
Received: 14 April 2019 / Revised: 30 May 2019 / Accepted: 4 June 2019 / Published: 12 June 2019
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Abstract

Endothelial dysfunction (ED) is an important contributor to atherosclerotic cardiovascular disease. Our previous study demonstrated that sphingomyelin synthase 2 (SMS2) promotes ED. Moreover, endoplasmic reticulum (ER) stress can lead to ED. However, whether there is a correlation between SMS2 and ER stress is unclear. To examine their correlation and determine the detailed mechanism of this process, we constructed a human umbilical vein endothelial cell (HUVEC) model with SMS2 overexpression. These cells were treated with 4-PBA or simvastatin and with LiCl and salinomycin alone. The results showed that SMS2 can promote the phosphorylation of lipoprotein receptor-related protein 6 (LRP6) and activate the Wnt/β-catenin pathway and that activation or inhibition of the Wnt/β-catenin pathway can induce or block ER stress, respectively. However, inhibition of ER stress by 4-PBA can decrease ER stress and ED. Furthermore, when the biosynthesis of cholesterol is inhibited by simvastatin, the reduction in intracellular cholesterol coincides with a decrease in ER stress and ED. Collectively, our results demonstrate that SMS2 can activate the Wnt/β-catenin pathway and promote intracellular cholesterol accumulation, both of which can contribute to the induction of ER stress and finally lead to ED. View Full-Text
Keywords: atherosclerosis; sphingomyelin synthase 2; endothelial dysfunction; endoplasmic reticulum stress; β-catenin atherosclerosis; sphingomyelin synthase 2; endothelial dysfunction; endoplasmic reticulum stress; β-catenin
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Hua, L.; Wu, N.; Zhao, R.; He, X.; Liu, Q.; Li, X.; He, Z.; Yu, L.; Yan, N. Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress. Int. J. Mol. Sci. 2019, 20, 2861.

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