Gene Transduction of an Active Mutant of Akt Exerts Cytoprotection and Reduces Graft Injury After Liver Transplantation

• Published in: American journal of transplantation Vol. 7; no. 4; pp. 769 - 778
• Main Authors: Morales‐Ruiz, M., Fondevila, C., Muñoz‐Luque, J., Tugues, S., Rodríguez‐Laiz, G., Cejudo‐Martín, P., Romero, J. M., Navasa, M., Fuster, J., Arroyo, V., Sessa, W. C., García‐Valdecasas, J. C., Jiménez, W.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-04-2007; Blackwell
• Subjects: Akt; Animals; Aorta; Biological and medical sciences; Cardiology. Vascular system; Cattle; Cell Line; Cells, Cultured; Endothelial Cells - cytology; Endothelial Cells - physiology; Endothelium, Vascular - cytology; Endothelium, Vascular - physiology; eNos; gene therapy; Hepatocytes - cytology; Hepatocytes - physiology; Humans; ischemia‐reperfusion insury; Kidney; liver transplantation; Medical sciences; Mutation; Oncogene Protein v-akt - genetics; Oncogene Protein v-akt - physiology; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Swine; eNos; ischemia- reperfusion insury; Digestive system; Liver; Ischemia reperfusion; Akt protein kinase; Transplantation; Akt; Homotransplantation; Trauma; Genetic transfer; Treatment; Surgery; Graft; Transduction; Lesion; Mutation; Gene therapy; liver transplantation
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01720.x

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.
In an experimental model of orthotopic liver transplantation in pigs, Akt activation exerts cytoprotection against ischemia‐reperfusion injury regardless of the Akt‐dependent activation of the endothelial nitric oxide synthase enzyme.