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Gene Transduction of an Active Mutant of Akt Exerts Cytoprotection and Reduces Graft Injury After Liver Transplantation
Author(s) -
MoralesRuiz M.,
Fondevila C.,
MuñozLuque J.,
Tugues S.,
RodríguezLaiz G.,
CejudoMartín P.,
Romero J. M.,
Navasa M.,
Fuster J.,
Arroyo V.,
Sessa W. C.,
GarcíaValdecasas J. C.,
Jiménez W.
Publication year - 2007
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2006.01720.x
Subject(s) - protein kinase b , enos , medicine , cytoprotection , liver transplantation , transplantation , nitric oxide , reperfusion injury , nitric oxide synthase , liver injury , apoptosis , pi3k/akt/mtor pathway , pharmacology , cancer research , endocrinology , biochemistry , ischemia , biology , oxidative stress
Akt is expected to be an effective target for the treatment of ischemia‐reperfusion injury (I/R) due to its anti‐apoptotic properties and its ability to activate the endothelial nitric oxide synthase (eNOS) enzyme. Therefore, this study was aimed to determine the efficacy of an active mutant of Akt (myr‐Akt) to decrease I/R injury in a model of orthotopic liver transplantation in pigs. In addition, we analyzed the contribution of nitric oxide in the Akt‐mediated effects by using an eNOS mutant (S1179DeNOS) that mimics the phosphorylation promoted by Akt in the eNOS sequence. Donors were treated with adenoviruses codifying for myr‐Akt, S1179DeNOS or β‐galactosidase 24 h before liver harvesting. Then, liver grafts were orthotopically transplanted into their corresponding recipients. Levels of transaminases and lactate dehydrogenase (LDH) increased in all recipients after 24 h of transplant. However, transaminases and LDH levels were significantly lower in the myr‐Akt group compared with vehicle. The percentage of apoptotic cells and the amount of activated‐caspase 3 protein were also markedly reduced in myr‐Akt‐treated grafts after 4 days of liver transplant compared with vehicle and S1179DeNOS groups. In conclusion, myr‐Akt gene therapy effectively exerts cytoprotection against hepatic I/R injury regardless of the Akt‐dependent eNOS activation.