Mutations to bid cleavage sites protect hepatocytes from apoptosis after ischemia/reperfusion injury.
Mutations to bid cleavage sites protect hepatocytes from apoptosis after ischemia/reperfusion injury.
复制标题
bid裂解位点突变可保护肝细胞在缺血/再灌注损伤后免于凋亡。
DOI：
10.1097/01.tp.0000281555.18782.2b
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发表时间：
2007
期刊：
影响因子：
6.2
通讯作者：
Krams,SheriM
中科院分区：
文献类型：
--
作者：
Riddle-Taylor,Erica;Nagasaki,Kazuhito;Lopez,Joseph;Esquivel,CarlosO;Martinez,OliviaM;Krams,SheriM
Background.Apoptosis of hepatocytes contributes to many forms of liver pathology and can compromise liver function. Hepatocytes have been shown to require mitochondrial disruption to execute apoptosis, a process that is controlled by members of the Bcl-2 family. Bid is a proapoptotic Bcl-2 family member that is cleaved to its active form, tBid, by caspase 8 and granzyme B. Studies in the Bid-deficient mouse have established that hepatocytes require Bid to undergo apoptosis.Methods.We generated aspartic acid to glutamic acid mutations in the rat Bid protein, at the caspase 8 and granzyme B cleavage sites, and utilized recombinant adenoviruses to express this protein in hepatoma cells and in the livers of rats.Results.Cells transduced with recombinant adenoviruses encoding Bid containing mutations to the caspase 8 and granzyme B cleavage sites are significantly protected from both tumor necrosis factor-α–induced and cell-mediated apoptosis. Protection occurs through a mechanism that includes decreased Bid cleavage, caspase activation, and mitochondrial membrane damage. Further, after warm ischemia/reperfusion injury, we show that rats expressing cleavage-resistant Bid in the liver display significantly less hepatocyte apoptosis as compared to control rat livers and this results in improved liver function and survival.Conclusion.Our results suggest that reagents that prevent the cleavage of Bid would be an effective strategy to inhibit hepatocyte apoptosis and decrease liver injury.
