TNF-alpha activates death pathway in human aorta smooth muscle cell in the presence of 7-ketocholesterol.
This study was undertaken to investigate whether a physiologically compatible concentration of 7-ketocholesterol had any effect on human vascular smooth muscle cells (HVSMCs). We found that 7-ketocholesterol changed the viability of human aorta smooth muscle cells (HAoSMC) not by cytotoxicity but by activation of tumor necrosis factor-alpha receptor (TNFR)-mediated death. Whereas TNF-alpha did not affect the viability in the presence of 7alpha-hydroxycholesterol or cholesterol, the cytokine induced HAoSMC death in the presence of 7-ketocholesterol as detected by morphology, viability, and fragmentation of chromosomal DNA. The HAoSMC death was inhibited by a neutralizing anti-TNF receptor 1 (TNFR1) antibody and by the caspase inhibitors of z-VAD and z-DEVD. Activations of caspase-8 and -3 were detected from dying HAoSMCs. 7-Ketocholesterol inhibited translocation of the nuclear factor kappaB (NF-kappaB) subunits of p65 and p50 from the cytosol into the nucleus, increase of NF-kappaB activity, and expression of caspase-8 homolog Fas ligand interleukin-1-converting enzyme inhibitory protein by TNF-alpha. We also found that X-chromosome-linked inhibitor of apoptosis protein was degraded in dying HAoSMC. The present study proposes that 7-ketocholesterol would contribute to the disappearance of HVSMC in the atherosclerotic lesions by enhancing receptor-mediated death. This is the first report demonstrating induction of TNF-alpha-mediated death by oxysterol in cells.
Laboratory of Lipid Metabolism, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Hyun Sun
HS
Lee
Jong Sun
JS
Chang
Jin Ah
JA
Baek
Mi Yeon
MY
Chung
Han Cheol
HC
Lee
Byung Yong
BY
Rhim
Dai Eun
DE
Sok
Mun-Chual
MC
Rho
Young Kook
YK
Kim
Koanhoi
K
Kim
D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007653:Ketocholesterols / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007653:Ketocholesterols; D014409:Tumor Necrosis Factor-alpha; C003001:7-ketocholesterol