|Title:||7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells||Authors:||Chang M.-C.
|Issue Date:||2016||Publisher:||Impact Journals LLC||Journal Volume:||7||Journal Issue:||46||Start page/Pages:||74473-74483||Source:||Oncotarget||Abstract:||
Cardiovascular 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.
|ISSN:||1949-2553||DOI:||10.18632/oncotarget.12578||SDG/Keyword:||7 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 Transduction
|Appears in Collections:||臨床牙醫學研究所|
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