Homocysteine induces programmed cell death in human vascular endothelial cells through activation of the unfolded protein response

被引:245
作者
Zhang, C
Cai, Y
Adachi, MT
Oshiro, S
Aso, T
Kaufman, RJ
Kitajima, S
机构
[1] Tokyo Med & Dent Univ, Med Res Inst, Dept Biochem Genet, Bunkyo Ku, Tokyo 1138510, Japan
[2] Japanese Fdn Canc Res, Inst Canc, Dept Viral Oncol, Toshima Ku, Tokyo 1708455, Japan
[3] Univ Michigan, Med Ctr, Dept Biol Chem, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Med Ctr, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
关键词
D O I
10.1074/jbc.M100747200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Severe hyperhomocysteinemia is associated with endothelial cell injury that may contribute to an increased incidence of thromboembolic disease. In this study, homocysteine induced programmed cell death in human umbilical vein endothelial cells as measured by TdT-mediated dUTP nick end labeling assay, DNA ladder formation, induction of caspase 3-like activity, and cleavage of procaspase 3. Homocysteine-induced cell death was specific to homocysteine, was not mediated by oxidative stress, and was mimicked by inducers of the unfolded protein response (UPR), a signal transduction pathway activated by the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum. Dominant negative forms of the endoplasmic reticulum-resident protein kinases IRE1 alpha and -beta, which function as signal transducers of the UPR prevented the activation of glucose-regulated protein 78/immunoglobulin chain-binding protein and C/EBP homologous protein/growth arrest and DNA damage-inducible protein 153 in response to homocysteine. Furthermore, overexpression of the point mutants of IRE1 with defective RNase more effectively suppressed the cell death than the kinase-defective mutant. These results indicate that homocysteine induces apoptosis in human umbilical vein endothelial cells by activation of the UPR and is signaled through IRE1. The studies implicate that the UPR may cause endothelial cell injury associated with severe hyperhomocysteinemia.
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页码:35867 / 35874
页数:8
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