Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase a Signaling Prevents Liver ischemia/reperfusion Injury in Mice

Liver Transpl. 2012 Jun;18(6):659-70. doi: 10.1002/lt.23399.

Abstract

Hepatic ischemia/reperfusion injury (IRI) occurs in multiple clinical settings, including liver transplantation. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway inhibits hepatocellular apoptosis and regulates toll-like receptor 4-triggered inflammation responses in vitro. Here we examined the function and therapeutic potential of cAMP-PKA activation in a murine (C57/BL6) model of liver warm ischemia (90 minutes) followed by reperfusion. Liver IRI triggered cAMP-PKA activation, whereas the administration of its specific inhibitor, H89, exacerbated hepatocellular damage. Conversely, forskolin therapy, which activates PKA by elevating cAMP levels, protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. Liver protection due to cAMP-PKA stimulation was accompanied by diminished neutrophil and macrophage infiltration/activation, reduced hepatocyte necrosis/apoptosis, and increased cAMP response element-binding protein (CREB) expression and augmented interleukin-10 (IL-10) expression. The neutralization of IL-10 restored liver damage in otherwise ischemia/reperfusion-resistant, forskolin-treated mice. In vitro, cAMP-PKA activation diminished macrophage tumor necrosis factor α, IL-6, and IL-12 in an IL-10-dependent manner and prevented necrosis/apoptosis in primary mouse hepatocyte cultures. Our novel findings in a mouse model of liver IRI document the importance of cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. The activation of cAMP-PKA signaling differentially regulates local inflammation and prevents hepatocyte death, and this provides a rationale for novel therapeutic approaches to combating liver IRI in transplant recipients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cells, Cultured
  • Colforsin / pharmacology*
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Interleukin-10 / metabolism
  • Isoquinolines / pharmacology
  • Liver / drug effects
  • Liver / enzymology
  • Liver / pathology
  • Liver Transplantation*
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Necrosis / metabolism
  • Necrosis / pathology
  • Necrosis / prevention & control
  • Peroxidase / metabolism
  • Reperfusion Injury* / metabolism
  • Reperfusion Injury* / pathology
  • Reperfusion Injury* / prevention & control
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Sulfonamides / pharmacology
  • Temperature

Substances

  • Enzyme Inhibitors
  • IL10 protein, mouse
  • Isoquinolines
  • Sulfonamides
  • Interleukin-10
  • Colforsin
  • Cyclic AMP
  • Peroxidase
  • Cyclic AMP-Dependent Protein Kinases
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide