SP1-dependent induction of CD39 facilitates hepatic ischemic preconditioning.
Ischemia/reperfusion injury (IRI) of the liver is an important cause of hepatic dysfunction. Ischemic preconditioning (IP) is associated with adenosine-mediated tissue protection from subsequent IRI. Extracellular nucleotides (e.g., ATP) represent the main source for extracellular adenosine. Therefore, we hypothesized that phosphohydrolysis of ATP/ADP via the ectonucleoside triphosphate diphosphohydrolase-1 (CD39), conversion of ATP/ADP to AMP, mediates IP-dependent liver protection. We found that hepatic IP was associated with significant induction of CD39 transcript, heightened protein expression, and improved outcomes after IRI. Targeted gene deletion or pharmacological inhibition of CD39 abolished hepatoprotection by IP as measured by serum markers of liver injury or histology. Therapeutic studies to mimic IP with i.p. apyrase (a soluble ectonucleoside triphosphate diphosphohydrolase, NTPDase) in the absence of IP attenuated hepatic injury after IRI. In additional in vivo studies, small interfering RNA treatment was used to achieve repression of the transcription factor Sp1, known to be implicated in CD39 transcriptional regulation. In fact, Sp1 small interfering RNA treatment was associated with attenuated CD39 induction and increased hepatic injury in vivo. Our data suggest a Sp1-dependent regulatory pathway for CD39 during hepatic IP. These studies reveal a novel role of CD39 in hepatic protection and suggest soluble apyrase for the treatment of liver ischemia.
Hart
Melanie L
ML
Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany. melaniehar@googlemail.com
Gorzolla
Iris C
IC
Schittenhelm
Jens
J
Robson
Simon C
SC
Eltzschig
Holger K
HK
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D001081:Apyrase / Q000378:metabolism* / Q000494:pharmacology; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007136:Immunoglobulins / Q000378:metabolism*; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015703:Antigens, CD; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; C090698:SP1 antigen; D001081:Apyrase; C067869:CD39 antigen