Chang M.-C.YI-JANE CHENLiou E.J.WAN-YU TSENGChan C.-P.Lin H.-J.Liao W.-C.Chang Y.-C.Jeng P.-Y.JIIANG-HUEI JENG2021-07-062021-07-0620161949-2553https://www.scopus.com/inward/record.uri?eid=2-s2.0-84996629626&doi=10.18632%2foncotarget.12578&partnerID=40&md5=29857e10f1cbf600ff9067882cce7d27https://scholars.lib.ntu.edu.tw/handle/123456789/569627Cardiovascular diseases (atherosclerosis, stroke, myocardiac infarction etc.) are the major systemic diseases of elder peoples in the world. This is possibly due to increased levels of oxidized low-density lipoproteins (oxLDLs) such as 7-ketocholesterol (7-KC) and lysophosphatidylcholine (LPC) that damage vascular endothelial cells, induce inflammatory responses, to elevate the risk of cardiovascular diseases, Alzheimer's disease, and age-related macular degeneration. However the toxic effects of 7-KC on endothelial cells are not known. In this study, 7-KC showed cytotoxicity to endothelial cells at concentrations higher than 10 μg/ml. 7-KC stimulated ATM/Chk2, ATR-Chk1 and p53 signaling pathways in endothelial cells. 7-KC also induced G0/G1 cell cycle arrest and apoptosis with an inhibition of Cyclin dependent kinase 1 (Cdk1) and cyclin B1 expression. Secretion and expression of IL-8 in endothelial cells were stimulated by 7-KC. 7-KC further induced intracellular ROS production as shown by increase in DCF fluorescence and Akt phosphorylation. LY294002 attenuated the 7-KC-induced apoptosis and IL-8 mRNA expression of endothelial cells. These results indicate that oxLDLs such as 7-KC may contribute to the pathogenesis of atherosclerosis, thrombosis and cardiovascular diseases by induction of endothelial damage, apoptosis and inflammatory responses. These events are associated with ROS production, activation of ATM/Chk2, ATR/Chk1, p53 and PI3K/Akt signaling pathways.[SDGs]SDG37 oxocholesterol; ATM protein; checkpoint kinase 1; checkpoint kinase 2; cyclin B1; interleukin 8; phosphatidylinositol 3 kinase; protein kinase B; protein p53; 7-ketocholesterol; ATM protein; biological marker; checkpoint kinase 1; checkpoint kinase 2; cholesterol derivative; cytokine; interleukin 8; phosphatidylinositol 3 kinase; protein kinase B; apoptosis; Article; atherosclerosis; cardiovascular disease; cell cycle arrest; controlled study; cytokine production; cytokine release; cytotoxicity; disease association; endothelium cell; enzyme activation; enzyme inhibition; enzyme phosphorylation; fluorescence analysis; G0 phase cell cycle arrest; G1 phase cell cycle checkpoint; gene; IL 8 gene; immune response; intracellular membrane; molecular pathology; protein expression; signal transduction; thrombosis; biosynthesis; cell cycle; cell survival; drug effects; endothelium cell; flow cytometry; gene expression; genetics; human; metabolism; signal transduction; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Biomarkers; Cell Cycle; Cell Survival; Checkpoint Kinase 1; Checkpoint Kinase 2; Cytokines; Endothelial Cells; Flow Cytometry; Gene Expression; Humans; Interleukin-8; Ketocholesterols; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transductionjournal article10.18632/oncotarget.12578277409382-s2.0-84996629626