Resistance to fas-induced apoptosis in cells from human atherosclerotic lesions: elevated Bcl-XL inhibits apoptosis and caspase activation.
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-X(L) 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-X(L)-transfected cells. Small-molecule Bcl-2/X(L) inhibitors and siRNA knockdown of Bcl-X(L) 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-X(L) 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.
Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA.
Zhaoqing
Z
Yang
Dmitry
D
Gagarin
Ali
A
Ramezani
Robert G
RG
Hawley
Timothy A
TA
McCaffrey
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020170:Caspase 1 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D005822:Genetic Vectors; D006801:Humans; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D046509:Tissue Culture Techniques; D014162:Transfection; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; C491901:FAS protein, human; D034741:RNA, Small Interfering; D050800:STAT6 Transcription Factor; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019014:fas Receptor; C505530:CASP8 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1