Resistance to fas-induced apoptosis in cells from human atherosclerotic lesions: Elevated Bcl-XL inhibits apoptosis and caspase activation
Journal of Vascular Research
Angioplasty; BAD; Bcl-X L; Caspase; Fas; Myocardial infarction; Restenosis; STAT6; Stroke
The inappropriate survival of cells in the neointima contributes to atherosclerotic plaque progression, while apoptosis in the fibrous cap of lesions contributes to myocardial infarction and stroke. Prior genomic-scale transcript profiling of human carotid artery plaque cells with known sensitivity or resistance to fas-induced apoptosis identified candidate genes involved in lesion cell apoptosis. Retroviral overexpression indicated that several candidate factors were not causative, but that Bcl-XL conferred complete resistance to apoptosis induced by fas ligation. Resistant cells failed to efficiently activate caspase 8, an effect which was also observed in Bcl-XL-transfected cells. Small-molecule Bcl-2/XL inhibitors and siRNA knockdown of Bcl-XL markedly sensitized resistant cells to apoptosis, and partially restored caspase 8 activation. Caspase 3, 6 and 9 inhibitors reduced caspase 8 activation and blocked apoptosis. Complete knockdown of caspase 9 did not reduce apoptosis, while knockdown of Bid suppressed apoptosis, suggesting that mitochondrial pathways independent of caspase 9, such as Smac/Diablo or AIF, provide a necessary mitochondrial input to efficient caspase activation. Bcl-XL appears to modulate lesion cell apoptosis by suppressing mitochondrial amplification of caspase activation loops. The results may have direct implications for controlling plaque instability/progression, and identify a new class of small molecules to inhibit restenosis. Copyright © 2007 S. Karger AG.
Yang, Z., Gagarin, D., Ramezani, A., Hawley, R., & McCaffrey, T. (2007). Resistance to fas-induced apoptosis in cells from human atherosclerotic lesions: Elevated Bcl-XL inhibits apoptosis and caspase activation. Journal of Vascular Research, 44 (6). http://dx.doi.org/10.1159/000106466