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.
Highlights
Ischemia/reperfusion injury (IRI) occurs as consequence of a temporary interruption of blood supply to an organ [1] and is a frequent complication of major liver surgery [2]
We investigated the effect of the stimulation of the A1 and A2A adenosine receptors on cell damage induced by cold hypoxic storage and subsequent warm reoxygenation of steatotic primary mice hepatocytes (S-HPs) by using the pharmacological agonists of the two adenosine receptors, CCPA and CGS21680, respectively
CGS21680 significantly reduced the cell damage of steatotic hepatocytes that were exposed to hypoxia/reoxygenation (HR); by contrast, CCPA significantly increased it (Figure 1A). These results show the capacity of the A2AR agonist CGS21680 to protect against the HR injury of steatotic hepatocytes, as well as that its protective activity is associated with a reduction in Apoptosis Signal-Regulating Kinase 1 (ASK1) and Jun N-terminal kinases (JNKs) activation
Summary
Ischemia/reperfusion injury (IRI) occurs as consequence of a temporary interruption of blood supply to an organ [1] and is a frequent complication of major liver surgery [2]. IRI can compromise liver function, increase postoperative morbidity and affect the overall outcome of patients [1,2]. The presence of steatosis greatly exacerbates hepatic IRI and represents a main risk factor of liver transplantation [3]. A strong predictor of liver failure after transplantation, but the shortage of donors often forces the acceptance of “marginal grafts” like fatty livers [2,3]. Hepatic steatosis is associated with an increased post-surgical mortality, no accepted therapeutic intervention is in use for the prevention of its deleterious effects [3]. Several pathogenic mechanisms might contribute to the increased hepatic IRI that is induced by fatty infiltration [4]. The upregulation of the mitochondrial uncoupling protein-2 with the increased production of oxidative species (OS) [5], the induction of endoplasmic reticulum stress (ERS) and the activation of inflammatory reactions play critical roles [6]
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