Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation.

Abstract

Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the effects of pharmacological A2AR and A1R activation. The A2AR agonist CGS21680 protected the primary steatotic murine hepatocyte from IR damage and the activation of ASK1 and JNK. Such an effect was attributed to a phosphatidylinositol-3-kinase (PI3K)/Akt-dependent inhibition of ASK1. By contrast, the A1R agonist CCPA enhanced IR damage, intracellular steatosis and oxidative species (OS) production, thereby further increasing the lipid/OS-dependent ASK1-JNK stimulation. The CGS2680 and CCPA effects were nullified by a genetic ASK1 downregulation in steatotic hepatoma C1C7 cells. In steatotic mice livers, CGS21680 protected against hepatic IRI and ASK1/JNK activation whereas CCPA aggravated hepatic steatosis and IRI, and enhanced ASK1 and JNK stimulation. These results evidence a novel mechanism of CGS21680-mediated hepatoprotection, i.e., the PI3K/AKT-dependent inhibition of ASK1, and they show that CGS21680 and CCPA reduces and enhances the IRI of fatty liver, respectively, by preventing or increasing the activation of the cytotoxic ASK1/JNK axis. They also indicate the selective employment of A2AR agonists as an effective therapeutic strategy to prevent IRI in human fatty liver surgery.

• Authors: Elisa Alchera, Bangalore R Chandrashekar, Nausicaa Clemente, Ester Borroni, Renzo Boldorini, Rita Carini
• Journal: Cells (Cells) Vol. 10 Issue 11 (11 15 2021) ISSN: 2073-4409 [Electronic] Switzerland
• PMID: 34831394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenosine A1 Receptor Agonists
• Adenosine A2 Receptor Agonists
• Lipids
• Protective Agents
• Receptor, Adenosine A1
• Receptor, Adenosine A2A
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• Map3k5 protein, mouse

Topics

• Adenosine A1 Receptor Agonists (pharmacology)
• Adenosine A2 Receptor Agonists (pharmacology)
• Animals
• Cell Death (drug effects)
• Cytoprotection (drug effects)
• Disease Progression
• Enzyme Activation (drug effects)
• Fatty Liver (complications)
• Gene Silencing
• Hepatocytes (drug effects, metabolism, pathology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lipids (analysis)
• MAP Kinase Kinase Kinase 5 (metabolism)
• Male
• Mice, Inbred BALB C
• Oxidation-Reduction
• Protective Agents (metabolism)
• Receptor, Adenosine A1 (metabolism)
• Receptor, Adenosine A2A (metabolism)
• Reperfusion Injury (complications)
• Mice