title: Lipid accumulation and lysosomal pathways contribute to dysfunction and apoptosis of human endothelial cells caused by 7-oxysterols.
abstract: Endothelial dysfunction and cell death play an important role in pathogenesis of atherosclerosis. 7-Oxysterols, the major cytotoxic component found in oxidized low-density lipoprotein, are toxic to endothelial cells. However, the pathways and molecular mechanism involved in the process remain incompletely understood. In this study, we first investigate whether 7β-hydroxycholesterol (7βOH) or 7-ketocholesterol (7keto) induces apoptosis of human endothelial cell line (HUVEC-CS). We then examine possible involved pathways by focusing on cellular lipid, lysosomal pathways, cellular oxidative stress and mitochondrial pathways. Our results for the first time showed that 7-oxysterols induced apoptotic cell death of HUVEC-CS after 24h, which was preceded by early lipid accumulation (6h) and lysosomal membrane permeabilization (6-12h). Afterward, levels of reactive oxygen species, mitochondrial membrane permeabilization, and lysosomal cathepsin were increased assayed by immuno-cytochemistry and blotting. Notably, the exposure to 7βOH or 7keto induced expressions and secretion of isoforms of von Willebrand factor (VWF). We conclude that apoptosis of HUVEC-CS induced by 7βOH or 7keto mediates by early lysosomal lipid accumulation and oxidative lysosomal pathways, which results in induction and release of VWF. The results suggest the cell death induced by 7-oxysterols may contribute to endothelial dysfunction and atherothrombosis.
authors.affiliation: Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping 581 85, Sweden. wei.li@liu.se
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Moumita
authors.initials: M
authors.lastname: Ghosh
authors.forename: Sina
authors.initials: S
authors.lastname: Eftekhari
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yuan
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000633:toxicity*; D007653:Ketocholesterols / Q000633:toxicity*; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*
chemical_list: D006888:Hydroxycholesterols; D007653:Ketocholesterols; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; C011724:cholest-5-en-3 beta,7 alpha-diol; D045304:Cytochromes c; C003001:7-ketocholesterol