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Title 

7-Ketocholesterol predisposes human aorta smooth muscle cells to Fas-mediated death

Authors 

Mun Chual RhoYoung Kook KimJong Sun ChangHyun Sun LeeJin Ah BaekMi Yeon ChungH C LeeH W LeeB Y RhimM A ReidyK Kim

Publisher 

Elsevier

Issue Date 

2005

Citation 

Journal of Molecular and Cellular Cardiology, vol. 39, no. 5, pp. 823-832

Keywords 

7-Ketocholesterolapoptosisatherosclerosisfasvascular smooth muscle cell7 oxocholesterolfas antibodyfas antigenfas associated death domain proteinprotein p37

Abstract 

Human vascular smooth muscle cells (HVSMCs) are resistant to Fas-mediated death under normal physiological conditions. However, HVSMC death by activation of the receptor pathway was reported in the atherosclerotic lesions. In this study, we investigated whether 7-ketocholesterol, one of the major cholesterol oxides in the lesions, altered resistance of HVSMC to Fas-mediated death pathway. Cross-linking of Fas receptor with agonistic anti-Fas antibody (CH11) in the presence of 7-ketocholesterol induced death in human aorta smooth muscle cells (HAoSMC) as detected by morphology, viability, and DNA fragmentation. The agonistic anti-Fas antibody, however, did not induce death in the presence of 7α-hydroxycholesterol or cholesterol. The HAoSMC death was significantly inhibited by an antagonistic Fas receptor (FasR) antibody and by expression of dominant negative Fas-associated death domain containing protein (DN-FADD) using adenoviruses. Activation of caspase-3 was observed in HAoSMC destined to death. HAoSMC death was significantly inhibited by pharmacological caspase inhibitor, z-VAD and z-DEVD, and baculovirus caspase inhibitor p35. 7-Ketocholesterol impaired mitochondrial transmembrane potential and ATP production. Overexpression of bcl-xL also significantly inhibited HAoSMC death. In dying HAoSMC, bax was translocated from the cytosol to mitochondria and cytochrome c was released from mitochondria into the cytosol. This is the first report demonstrating implication of the oxysterol in Fas-mediated death pathway. The present study proposes that 7-ketocholesterol would contribute to loss of HVSMC in the atherosclerotic lesions by altering resistance to receptor-mediated death pathway.

ISSN 

0022-2828

Link 

http://dx.doi.org/10.1016/j.yjmcc.2005.07.018

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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