Ischemic preconditioning of the murine liver protects through the Akt kinase pathway

Hepatic ischemia‐reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt‐signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20‐minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase β, and caspase‐3. In addition, IPC also inhibited the activities of c‐Jun N‐terminal kinase and nuclear factor κB after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2006;44:573–580.)

[1]  G. Gores,et al.  Apoptosis and necrosis in the liver: A tale of two deaths? , 2006, Hepatology.

[2]  G. Semenza,et al.  PTEN Activity Is Modulated During Ischemia and Reperfusion: Involvement in the Induction and Decay of Preconditioning , 2005, Circulation research.

[3]  M. Lotze,et al.  Hepatic Ischemia/Reperfusion Injury Involves Functional TLR4 Signaling in Nonparenchymal Cells1 , 2005, The Journal of Immunology.

[4]  D. Chung,et al.  Signal Transduction Pathways Involved in Oxidative Stress-Induced Intestinal Epithelial Cell Apoptosis , 2005, Pediatric Research.

[5]  D. Brenner,et al.  JNK mediates hepatic ischemia reperfusion injury. , 2005, Journal of hepatology.

[6]  K. Tracey,et al.  The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion , 2005, The Journal of experimental medicine.

[7]  Ryan M. O’Connell,et al.  Cutting Edge: TLR4 Activation Mediates Liver Ischemia/Reperfusion Inflammatory Response via IFN Regulatory Factor 3-Dependent MyD88-Independent Pathway1 , 2004, The Journal of Immunology.

[8]  P. Greengard,et al.  Pharmacological inhibitors of glycogen synthase kinase 3. , 2004, Trends in pharmacological sciences.

[9]  M. Nitti,et al.  Role of phosphatidylinositol 3-kinase in the development of hepatocyte preconditioning. , 2004, Gastroenterology.

[10]  Y. Fujio,et al.  Taurine prevents the ischemia-induced apoptosis in cultured neonatal rat cardiomyocytes through Akt/caspase-9 pathway. , 2004, Biochemical and biophysical research communications.

[11]  L. Chao,et al.  Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling , 2004, Hypertension.

[12]  T. Kálai,et al.  Impact of a novel cardioprotective agent on the ischaemia-reperfusion-induced Akt kinase activation. , 2003, Biochemical pharmacology.

[13]  H. Rüdiger,et al.  Sub-lethal oxidative stress triggers the protective effects of ischemic preconditioning in the mouse liver. , 2003, Journal of hepatology.

[14]  H. Jaeschke,et al.  Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. , 2003, Gastroenterology.

[15]  A. Vollmar,et al.  α-Lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway , 2003 .

[16]  N. Selzner,et al.  Protective strategies against ischemic injury of the liver. , 2003, Gastroenterology.

[17]  R. Busuttil,et al.  Hepatic ischemia/reperfusion injury--a fresh look. , 2003, Experimental and molecular pathology.

[18]  S. Qin,et al.  Implication of phosphatidylinositol 3-kinase membrane recruitment in hydrogen peroxide-induced activation of PI3K and Akt. , 2003, Biochemistry.

[19]  H. Maeta,et al.  Significance of phosphoinositide 3-kinase pathway on ischemic preconditioning followed by ischemia reperfusion in mice liver. , 2003, Transplantation Proceedings.

[20]  S. Todo,et al.  A novel inhibitor of Rho-associated protein kinase, Y-27632, ameliorates hepatic ischemia and reperfusion injury in rats. , 2003, Surgery.

[21]  I. Leclercq,et al.  Low‐dose TNF‐α protects against hepatic ischemia‐reperfusion injury in mice: Implications for preconditioning , 2003, Hepatology.

[22]  P. Dennis,et al.  Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. , 2002, Molecular cancer therapeutics.

[23]  Woojin Jeong,et al.  Reversible Inactivation of the Tumor Suppressor PTEN by H2O2 * , 2002, The Journal of Biological Chemistry.

[24]  H. Rüdiger,et al.  Comparison of Ischemic Preconditioning and Intermittent and Continuous Inflow Occlusion in the Murine Liver , 2002, Annals of surgery.

[25]  D. Yellon,et al.  Myocardial Protection by Insulin at Reperfusion Requires Early Administration and Is Mediated via Akt and p70s6 Kinase Cell-Survival Signaling , 2001, Circulation research.

[26]  J. Gugenheim,et al.  Intermittent ischemia reduces warm hypoxia‐reoxygenation–induced JNK1/SAPK1 activation and apoptosis in rat hepatocytes , 2001, Hepatology.

[27]  J. Woodgett,et al.  PKB/AKT: functional insights from genetic models , 2001, Nature Reviews Molecular Cell Biology.

[28]  K. Fukunaga,et al.  Activation of Akt/Protein Kinase B Contributes to Induction of Ischemic Tolerance in the CA1 Subfield of Gerbil Hippocampus , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[29]  N. Habib,et al.  Hepatic ischemia-reperfusion injury. , 2001, American journal of surgery.

[30]  A. Farhood,et al.  Mechanism of cell death during warm hepatic ischemia‐reperfusion in rats: Apoptosis or necrosis? , 2001, Hepatology.

[31]  I. Kang,et al.  Insulin-like growth factor-1 protects H9c2 cardiac myoblasts from oxidative stress-induced apoptosis via phosphatidylinositol 3-kinase and extracellular signal-regulated kinase pathways. , 2001, Life sciences.

[32]  W. Zhu,et al.  Insulin Prevents Cardiomyocytes From Oxidative Stress–Induced Apoptosis Through Activation of PI3 Kinase/ Akt , 2000, Circulation.

[33]  K. Kato,et al.  Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. , 2000, Cancer research.

[34]  R. Bentley,et al.  Protective Effects of Ischemic Preconditioning for Liver Resection Performed Under Inflow Occlusion in Humans , 2000, Annals of surgery.

[35]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[36]  D. Sindram,et al.  Ischemic preconditioning protects the mouse liver by inhibition of apoptosis through a caspase‐dependent pathway , 1999, Hepatology.

[37]  Richard A. Roth,et al.  Regulation of GLUT1 Gene Transcription by the Serine/Threonine Kinase Akt1* , 1999, The Journal of Biological Chemistry.

[38]  T. Soderling,et al.  Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway , 1998, Nature.

[39]  Philip R. Cohen,et al.  The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. , 1998, The Biochemical journal.

[40]  J. Woodgett,et al.  Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  F. Ismail-Beigi,et al.  Dual Control of glut1 Glucose Transporter Gene Expression by Hypoxia and by Inhibition of Oxidative Phosphorylation* , 1997, The Journal of Biological Chemistry.

[42]  P. Cohen,et al.  Mechanism of activation of protein kinase B by insulin and IGF‐1. , 1996, The EMBO journal.

[43]  A. Klip,et al.  Mechanisms of adaptation of glucose transporters to changes in the oxidative chain of muscle and fat cells. , 1993, The American journal of physiology.

[44]  R. Bünger,et al.  Glucose requirement for postischemic recovery of perfused working heart. , 1990, European journal of biochemistry.

[45]  Hartmut Jaeschke,et al.  Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning. , 2003, American journal of physiology. Gastrointestinal and liver physiology.

[46]  A. Vollmar,et al.  Alpha-lipoic acid preconditioning reduces ischemia-reperfusion injury of the rat liver via the PI3-kinase/Akt pathway. , 2003, American journal of physiology. Gastrointestinal and liver physiology.