title: The influence of phosphatidylinositol 3-kinase/Akt pathway on the ischemic injury during rat liver graft preservation.
abstract: We aimed to investigate the role of phosphatidylinositol 3 (PI3)-kinase/Akt pathway on ischemic injury. Rat liver grafts were preserved in UW solution with different treatments and were compared by 1-week survival rates and morphological changes with those of the control group. PI3-kinase/Akt was significantly activated at the sites of Thr 308 and Ser 473 in the preserved grafts. Downstream target proteins, glycogen synthase kinase-3beta (GSK-3beta) and caspase-9, were inactivated. However, survival signal transduction from Akt to Bad was blocked by calcium release after activation of PI3-kinase/Akt. Significant activation of caspase-12, -3 and -7 contributed to cell apoptosis and severe ischemic injury was shown after 7 h of preservation by UW solution with insulin. Downregulation of phospho-Akt at Thr 308 and Ser 473 was due to partial inhibition of PI3-kinase/Akt pathway by LY294002. Activation of GSK-3beta and inactivation of caspase-12 and Bad could be found in the LY294002 groups in which the liver grafts showed less ischemic injury. Higher 1-week survival rates in the heparin, LY294002, and glucagon groups confirmed the dysregulation of the pathway. In conclusion, PI3-kinase/Akt pathway was dysregulated and contributed to ischemic injury during preservation. Heparin and LY294002 could improve graft viability by maintaining calcium homeostasis during preservation.
authors.affiliation: Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Republic of China. lix1@graduate.hku.hk
authors.forename: Xian Liang
authors.initials: XL
authors.lastname: Li
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Ng
authors.forename: Chris K
authors.initials: CK
authors.lastname: Sun
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006085:Graft Survival; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology; D016031:Liver Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051025:bcl-Associated Death Protein
chemical_list: D002118:Calcium; D002352:Carrier Proteins; D020169:Caspases; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051025:bcl-Associated Death Protein; C494821:Bad protein, rat; C494920:Akt1 protein, rat; C000605508:Gsk3b protein, rat