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Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress

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 E...

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Detalles Bibliográficos
Autores principales: Hua, Lingyue, Wu, Na, Zhao, Ruilin, He, Xuanhong, Liu, Qian, Li, Xiatian, He, Zhiqiang, Yu, Lehan, Yan, Nianlong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627305/
https://www.ncbi.nlm.nih.gov/pubmed/31212751
http://dx.doi.org/10.3390/ijms20122861
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author Hua, Lingyue
Wu, Na
Zhao, Ruilin
He, Xuanhong
Liu, Qian
Li, Xiatian
He, Zhiqiang
Yu, Lehan
Yan, Nianlong
author_facet Hua, Lingyue
Wu, Na
Zhao, Ruilin
He, Xuanhong
Liu, Qian
Li, Xiatian
He, Zhiqiang
Yu, Lehan
Yan, Nianlong
author_sort Hua, Lingyue
collection PubMed
description 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.
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spelling pubmed-66273052019-07-23 Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress Hua, Lingyue Wu, Na Zhao, Ruilin He, Xuanhong Liu, Qian Li, Xiatian He, Zhiqiang Yu, Lehan Yan, Nianlong Int J Mol Sci Article 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. MDPI 2019-06-12 /pmc/articles/PMC6627305/ /pubmed/31212751 http://dx.doi.org/10.3390/ijms20122861 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hua, Lingyue
Wu, Na
Zhao, Ruilin
He, Xuanhong
Liu, Qian
Li, Xiatian
He, Zhiqiang
Yu, Lehan
Yan, Nianlong
Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress
title Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress
title_full Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress
title_fullStr Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress
title_full_unstemmed Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress
title_short Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress
title_sort sphingomyelin synthase 2 promotes endothelial dysfunction by inducing endoplasmic reticulum stress
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627305/
https://www.ncbi.nlm.nih.gov/pubmed/31212751
http://dx.doi.org/10.3390/ijms20122861
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