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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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.[1]


  1. TNF-alpha activates death pathway in human aorta smooth muscle cell in the presence of 7-ketocholesterol. Lee, H.S., Chang, J.S., Baek, J.A., Chung, M.Y., Lee, H.C., Rhim, B.Y., Sok, D.E., Rho, M.C., Kim, Y.K., Kim, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
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