Protective Effect of Ergothioneine against 7-Ketocholesterol-Induced Mitochondrial Damage in hCMEC/D3 Human Brain Endothelial Cells

被引:7
作者
Leow, Damien Meng-Kiat [1 ,2 ]
Cheah, Irwin Kee-Mun [2 ,3 ]
Fong, Zachary Wei-Jie [2 ,3 ]
Halliwell, Barry [2 ,3 ]
Ong, Wei-Yi [1 ,2 ]
机构
[1] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, Singapore 117594, Singapore
[2] Natl Univ Singapore, Life Sci Inst, Neurobiol Res Programme, Singapore 117456, Singapore
[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117596, Singapore
基金
英国医学研究理事会;
关键词
ergothioneine; 7-ketocholesterol; oxysterols; cytoprotection; ALZHEIMERS-DISEASE; OXIDATIVE DAMAGE; CALCIUM; OXYSTEROLS; BARRIER; CHOLESTEROL; INVOLVEMENT; DYSFUNCTION; ANTIOXIDANT; APOPTOSIS;
D O I
10.3390/ijms24065498
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recent findings have suggested that the natural compound ergothioneine (ET), which is synthesised by certain fungi and bacteria, has considerable cytoprotective potential. We previously demonstrated the anti-inflammatory effects of ET on 7-ketocholesterol (7KC)-induced endothelial injury in human blood-brain barrier endothelial cells (hCMEC/D3). 7KC is an oxidised form of cholesterol present in atheromatous plaques and the sera of patients with hypercholesterolaemia and diabetes mellitus. The aim of this study was to elucidate the protective effect of ET on 7KC-induced mitochondrial damage. Exposure of human brain endothelial cells to 7KC led to a loss of cell viability, together with an increase in intracellular free calcium levels, increased cellular and mitochondrial reactive oxygen species, a decrease in mitochondrial membrane potential, reductions in ATP levels, and increases in mRNA expression of TFAM, Nrf2, IL-1 beta, IL-6 and IL-8. These effects were significantly decreased by ET. Protective effects of ET were diminished when endothelial cells were coincubated with verapamil hydrochloride (VHCL), a nonspecific inhibitor of the ET transporter OCTN1 (SLC22A4). This outcome demonstrates that ET-mediated protection against 7KC-induced mitochondrial damage occurred intracellularly and not through direct interaction with 7KC. OCTN1 mRNA expression itself was significantly increased in endothelial cells after 7KC treatment, consistent with the notion that stress and injury may increase ET uptake. Our results indicate that ET can protect against 7KC-induced mitochondrial injury in brain endothelial cells.
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页数:15
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