The influence of phosphatidylinositol 3-kinase/Akt pathway on the ischemic injury during rat liver graft preservation

Am J Transplant. 2005 Jun;5(6):1264-75. doi: 10.1111/j.1600-6143.2005.00877.x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Calcium / metabolism*
  • Carrier Proteins / metabolism
  • Caspases / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Graft Survival*
  • Ischemia / metabolism*
  • Ischemia / pathology
  • Liver Transplantation*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Inbred Lew
  • Reperfusion Injury / metabolism*
  • Reperfusion Injury / pathology
  • Signal Transduction*
  • bcl-Associated Death Protein

Substances

  • Bad protein, rat
  • Carrier Proteins
  • Proto-Oncogene Proteins
  • bcl-Associated Death Protein
  • Phosphatidylinositol 3-Kinases
  • Akt1 protein, rat
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Caspases
  • Calcium