Secosterol-B affects endoplasmic reticulum structure in endothelial cells. Issue 190 (June 2019)

• Record Type: Journal Article
• Authors: Luchetti, Francesca; Crinelli, Rita; Nasoni, Maria Gemma; Cesarini, Erica; Canonico, Barbara; Guidi, Loretta; Zerbinati, Chiara; Magnani, Mauro; Papa, Stefano; Iuliano, Luigi
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 190(2019)
• Page Start: 234
• Page End: 241
• Publication Date: 2019-06
• Subjects: ANNEX-V AnnexinV -- EC endothelial cells -- eIF2α translation eukaryotic initiation factor 2 -- ER endoplasmic reticulum -- FC flow cytometry -- GFP green fluorescent protein -- HUVEC human umbilical vein endothelial cells -- ISR integrated stress response -- MDC monodansylcadaverine -- OxLDL oxidized low-density lipoprotein -- PI propidium iodide -- SEC-B 3β-hydroxy-5β-hydroxy-B-norcholestane-6β-carboxaldehyde secosterol-B -- SDS Sodium dodecyl sulfate -- UPR the unfolded protein response -- UPS ubiquitin/proteasome system; Endoplasmic reticulum -- Oxysterols -- Autophagy -- Apoptosis -- eIF2α -- NF-kB; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.04.014
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Secosterol-B induces ER stress in HUVEC. Secosterol-B triggers pro-survival signaling through autophagy and UPS. eIF2α phosphorylation and NF-kB activation involved in the secosterol-B-induced apoptosis. Abstract: Oxysterols, oxidized derivatives of cholesterol found in LDL and atherosclerotic plaques, trigger several biological responses involved in the initiation and progression of atherosclerosis. Endothelial dysfunction, which occurs when vascular homeostasis is altered, plays a key role in the pathogenesis of several metabolic diseases. The contribution of endoplasmic reticulum (ER) stress to endothelial disfunction is a relatively recent area of investigation. There is a well-established link between LDL oxidation and ER stress but the role played by specific products of lipid oxidation into this interaction is still to be defined. The present study shows that secosterol-B (SEC-B), 3β-hydroxy-5β-hydroxy-B-norcholestane-6βcarboxaldehyde, a cholesterol autoxidation product recently identified in the atherosclerotic plaque, is able to induce ER stress in HUVEC cells, as revealed by significant expansion and change of structure. At low doses, i.e. 1 and 5 μM, cells try to cope with this stress by activating autophagy and the ubiquitin proteasome system in the attempt to restore ER function. However, at higher doses, i.e. 20 μM, cell apoptosis occurs in a pathway that involves early phosphorylation of eIF2α and NF-kB activation, suggesting that the adaptive program fails and the cell activates the apoptotic program. These findings provide additional insight about the role of oxysterols in endothelial dysfunction and its potential involvement in atherosclerotic pathophysiology.