title: 7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells.
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.
authors.affiliation: Biomedical Science Team, Chang Gung University of Science and Technology, Kwei-Shan, Taoyuan, Taiwan.|Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Mei-Chi
authors.initials: MC
authors.lastname: Chang
authors.affiliation: School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yi-Jane
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Eric Jein-Wein
authors.initials: EJ
authors.lastname: Liou
authors.affiliation: School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Tseng
authors.affiliation: Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan.
authors.forename: Chiu-Po
authors.initials: CP
authors.lastname: Chan
authors.affiliation: Department of Dentistry, Show Chwan Memorial Hospital, Changhua, Taiwan.
authors.forename: Hseuh-Jen
authors.initials: HJ
authors.lastname: Lin
authors.affiliation: School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wan-Chuen
authors.initials: WC
authors.lastname: Liao
authors.affiliation: Department of Dentistry, Mackey Memorial Hospital, Taipei, Taiwan.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Chang
authors.affiliation: School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Po-Yuan
authors.initials: PY
authors.lastname: Jeng
authors.affiliation: School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jiiang-Huei
authors.initials: JH
authors.lastname: Jeng
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D007653:Ketocholesterols / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D016207:Cytokines; D016209:Interleukin-8; D007653:Ketocholesterols; D019869:Phosphatidylinositol 3-Kinases; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; D051057:Proto-Oncogene Proteins c-akt; C003001:7-ketocholesterol
keywords: Gerotarget; apoptosis; atherosclerosis; cytotoxicity; endothelial cells; inflammation