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Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2019 Jun 12; Vol. 20 (12). Date of Electronic Publication: 2019 Jun 12. - Publication Year :
- 2019
-
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.
- Subjects :
- Biomarkers
Cell Adhesion drug effects
Cells, Cultured
Endothelium, Vascular physiopathology
Human Umbilical Vein Endothelial Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacology
Membrane Proteins genetics
Nerve Tissue Proteins genetics
Phosphorylation
Simvastatin pharmacology
Transferases (Other Substituted Phosphate Groups) genetics
Wnt Signaling Pathway
beta Catenin metabolism
Endoplasmic Reticulum Stress
Endothelium, Vascular drug effects
Endothelium, Vascular metabolism
Membrane Proteins metabolism
Nerve Tissue Proteins metabolism
Transferases (Other Substituted Phosphate Groups) metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 20
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 31212751
- Full Text :
- https://doi.org/10.3390/ijms20122861