Oncotarget

Research Papers: Gerotarget (Focus on Aging):

7-Ketocholesterol induces ATM/ATR, Chk1/Chk2, PI3K/Akt signalings, cytotoxicity and IL-8 production in endothelial cells

Mei-Chi Chang, Yi-Jane Chen, Eric Jein-Wein Liou, Wan-Yu Tseng, Chiu-Po Chan, Hseuh-Jen Lin, Wan-Chuen Liao, Ya-Ching Chang, Po-Yuan Jeng and Jiiang-Huei Jeng _

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Oncotarget. 2016; 7:74473-74483. https://doi.org/10.18632/oncotarget.12578

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Abstract

Mei-Chi Chang1,2, Yi-Jane Chen3,*, Eric Jein-Wein Liou2, Wan-Yu Tseng3, Chiu-Po Chan2, Hseuh-Jen Lin4, Wan-Chuen Liao3, Ya-Ching Chang5, Po-Yuan Jeng3 and Jiiang-Huei Jeng3

1 Biomedical Science Team, Chang Gung University of Science and Technology, Kwei-Shan, Taoyuan, Taiwan

2 Department of Dentistry, Chang Gung Memorial Hospital, Taipei, Taiwan

3 School of Dentistry and Department of Dentistry, National Taiwan University Medical College and National Taiwan University Hospital

4 Department of Dentistry, Show Chwan Memorial Hospital, Changhua, Taiwan

5 Department of Dentistry, Mackey Memorial Hospital, Taipei, Taiwan

* This author have contributes equally to the first author

Correspondence to:

Jiiang-Huei Jeng, email:

Chiu-Po Chan, email:

Keywords: apoptosis, atherosclerosis, cytotoxicity, endothelial cells, inflammation,Gerotarget

Received: September 13, 2016 Accepted: October 06, 2016 Published: October 11, 2016

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.


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