Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-07, Vol.110 (29), p.12012-12017
• Main Authors: Zimmerman, Michael A., Grenz, Almut, Tak, Eunyoung, Kaplan, Maria, Ridyard, Douglas, Brodsky, Kelley S., Mandell, Mercedes Susan, Kam, Igal, Eltzschig, Holger K.
• Format: Article
• Language: English
• Subjects: Agonists; Animals; Biological Sciences; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Gene Expression Profiling; Humans; Hypoxia; Immunoblotting; Inflammation; Ischemia; Liver; Liver - metabolism; Liver - physiopathology; Liver diseases; Medical treatment; Mice; Mice, Knockout; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Physical trauma; Purinergic P1 receptors; Receptor, Adenosine A2B - genetics; Receptor, Adenosine A2B - metabolism; Reperfusion; Reperfusion injury; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Rodents; Signal Transduction - physiology; Transcriptional regulatory elements
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1221733110

Ischemia and reperfusion significantly contributes to the morbidity and mortality of liver surgery and transplantation. Based on studies showing a critical role for adenosine signaling in mediating tissue adaptation during hypoxia, we hypothesized that signaling events through adenosine receptors (ADORA1, ADORA2A, ADORA2B, or ADORA3) attenuates hepatic ischemia and reperfusion injury. Initial screening studies of human liver biopsies obtained during hepatic transplantation demonstrated a selective and robust induction of ADORA2B transcript and protein following ischemia and reperfusion. Subsequent exposure of gene-targeted mice for each individual adenosine receptor to liver ischemia and reperfusion revealed a selective role for the Adora2b in liver protection. Moreover, treatment of wild-type mice with an Adora2b-selective antagonist resulted in enhanced liver injury, whereas Adora2b-agonist treatment was associated with attenuated hepatic injury in wild-type, but not in Adora2b ⁻/⁻ mice. Subsequent studies in mice with Adora2b deletion in different tissues—including vascular endothelia, myeloid cells, and hepatocytes—revealed a surprising role for hepatocellular-specific Adora2b signaling in attenuating nuclear factor NF-κB activation and thereby mediating liver protection from ischemia and reperfusion injury. These studies provide a unique role for hepatocellular-specific Adora2b signaling in liver protection during ischemia and reperfusion injury.