Upregulation of Bag-1 by ex vivo gene transfer protects rat livers from ischemia/reperfusion injury.
Bag-1 exerts powerful antiapoptotic effects by binding and stabilizing Bcl-2 and interacting with the tumor necrosis factor receptor type I-induced death signal. We examined the effects of overexpression of Bag-1 by ex vivo adenoviral gene transfer on cold (4 degrees C for 24 hr) ischemia/reperfusion (I/R) injury of rat livers. Treatment with adenoviral Bag-1 (Ad-Bag-1) significantly improved portal venous blood flow, increased bile production, and improved hepatic function in the ex vivo model of cold ischemia followed by isolated perfusion. Moreover, the survival of orthotopic liver grafts subjected to cold ischemia increased from 50% in Ad-betaGal-treated controls to 100% after Ad-Bag-1 therapy. This effect correlated with preserved hepatic architecture, improved liver function, and depressed infiltration by neutrophils. Furthermore, the activation of infiltrating T cells, as measured by CD25, IL-2, and IFN-gamma mRNA expression was markedly reduced in the Ad-Bag-1 group. Hence, gene therapy-induced Bag-1 overexpression prevented cold I/R injury in rat livers. These findings provide the rationale for refined novel treatment of donor livers and may ultimately improve the overall success of liver transplantation.
Sawitzki
Birgit
B
Nuffield Department of Surgery, John Radcliffe Hospital, Oxford University, UK. brigit.sawitzki@surgery.ox.ac.uk
Amersi
Farin
F
Ritter
Thomas
T
Fisser
Marion
M
Shen
Xiu-Da
XD
Ke
Bibo
B
Busuttil
Ronald
R
Volk
Hans-Dieter
HD
Kupiec-Weglinski
Jerzy W
JW
D000256:Adenoviridae; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics*
C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha