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Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
- Source :
- Cells, Cells; Volume 10; Issue 11; Pages: 3171, Cells, Vol 10, Iss 3171, p 3171 (2021)
- Publication Year :
- 2021
- Publisher :
- MDPI, 2021.
-
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.
- Subjects :
- Agonist
Male
Adenosine A2 Receptor Agonists
Receptor, Adenosine A2A
QH301-705.5
medicine.drug_class
hepatocyte death
Pharmacology
ischemia/reperfusion injury
MAP Kinase Kinase Kinase 5
Protective Agents
Article
survival pathways
chemistry.chemical_compound
medicine
steatosis
hepatic damage
oxidative stress
Animals
hepatoprotection
Gene Silencing
Biology (General)
adenosine receptor
Mice, Inbred BALB C
Cell Death
Chemistry
Receptor, Adenosine A1
Fatty liver
JNK Mitogen-Activated Protein Kinases
General Medicine
medicine.disease
Lipids
Adenosine A1 Receptor Agonists
Transplantation
Enzyme Activation
Fatty Liver
medicine.anatomical_structure
Hepatoprotection
Cytoprotection
Hepatocyte
Reperfusion Injury
CCPA
Disease Progression
Hepatocytes
Steatosis
Reperfusion injury
Oxidation-Reduction
Subjects
Details
- Language :
- English
- ISSN :
- 20734409
- Volume :
- 10
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Cells
- Accession number :
- edsair.doi.dedup.....6c4573ef6f4a63cd5f27494fe7b9d897