Sensitivity to Fas-mediated apoptosis is determined below receptor level in human vascular smooth muscle cells

被引:51
作者
Chan, SW
Hegyi, L
Scott, S
Cary, NRB
Weissberg, PL
Bennett, MR
机构
[1] Addenbrookes Hosp, Addenbrookes Ctr Clin Invest, Unit Cardiovasc Med, Cambridge CB2 2QQ, England
[2] Papworth Hosp, Dept Histopathol, Cambridge CB3 8RE, England
关键词
vascular smooth muscle cell; apoptosis; remodeling;
D O I
10.1161/01.RES.86.10.1038
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Despite Fas expression, many cells resist Fas-induced apoptosis, Although differences in surface Fas expression can explain Fas resistance, multiple proteins below receptor level also inhibit Fas-induced apoptosis, To examine the mechanism of Fas resistance, we studied Fas-induced apoptosis in human medial vascular smooth muscle cells (VSMCs) from healthy coronary arteries. VSMCs showed marked heterogeneity to Fas-induced apoptosis, exhibiting both Fas-resistant (98.1+/-2.3% viable, n=4, P=NS) and Fas-sensitive (31.3+/-2.6% viable, n=3, P<0.01) cells. Fas-resistant VSMCs expressed surface Pas and could recruit RIP, indicating that functional receptor complexes were formed. However, Fas-resistant cells showed reduced expression of FADD, Fas ligand, and caspases 3, 7, and 8 and increased expression of FLIP and c-IAP-1. Fas-induced apoptosis was associated with cleavage of caspase 3 and blocked by inhibitors of caspase 3 or 8 but not caspase 1, 6, or 7, Selective inhibition of caspase 3 or 8 by antisense transfection inhibited Fas-induced apoptosis, but their reexpression could not rescue the Fas-resistant phenotype, In vivo, medial VSMCs showed marked heterogeneity of expression of caspase 3, We conclude that Pas sensitivity is determined not only by expression of surface Fas but by differential expression of Fas-signaling proteins below receptor level. Subpopulations of cells within the same tissue have different sensitivities to apoptosis, determined by expression of specific death-signaling proteins.
引用
收藏
页码:1038 / 1046
页数:9
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