Sphingomyelin Synthase 2 Promotes Endothelial Dysfunction by Inducing Endoplasmic Reticulum Stress

• Published in: International journal of molecular sciences Vol. 20; no. 12; p. 2861
• Main Authors: Hua, Lingyue, Wu, Na, Zhao, Ruilin, He, Xuanhong, Liu, Qian, Li, Xiatian, He, Zhiqiang, Yu, Lehan, Yan, Nianlong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.06.2019; MDPI
• Subjects: Atherosclerosis; beta Catenin - metabolism; Biomarkers; Biosynthesis; Cell Adhesion - drug effects; Cell fate; Cell proliferation; Cells, Cultured; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endothelial cells; endothelial dysfunction; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Enzymes; Frizzled protein; Homeostasis; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen peroxide; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oxidative stress; Pattern formation; Phosphorylation; Plasmids; Protein expression; Proteins; Receptor density; Signal processing; Signal transduction; Simvastatin - pharmacology; Sphingomyelin; sphingomyelin synthase 2; Transferases (Other Substituted Phosphate Groups) - genetics; Transferases (Other Substituted Phosphate Groups) - metabolism; Umbilical vein; Wnt protein; Wnt Signaling Pathway; β-Catenin; atherosclerosis; β-catenin; endothelial dysfunction; endoplasmic reticulum stress; sphingomyelin synthase 2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20122861

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.