title: Adora2b signaling on bone marrow derived cells dampens myocardial ischemia-reperfusion injury.
abstract: BACKGROUND
  Cardiac ischemia-reperfusion (I-R) injury represents a major cause of cardiac tissue injury. Adenosine signaling dampens inflammation during cardiac I-R. The authors investigated the role of the adenosine A2b-receptor (Adora2b) on inflammatory cells during cardiac I-R.
  
  
  METHODS
  To study Adora2b signaling on inflammatory cells, the authors transplanted wild-type (WT) bone marrow (BM) into Adora2b(-/-) mice or Adora2b(-/-) BM into WT mice. To study the role of polymorphonuclear leukocytes (PMNs), neutrophil-depleted WT mice were treated with an Adora2b agonist. After treatments, mice were exposed to 60 min of myocardial ischemia and 120 min of reperfusion. Infarct sizes and troponin I concentrations were determined by triphenyltetrazolium chloride staining and enzyme-linked immunosorbent assay, respectively.
  
  
  RESULTS
  Transplantation of WT BM into Adora2b(-/-) mice decreased infarct sizes by 19 ± 4% and troponin I by 87.5 ± 25.3 ng/ml (mean ± SD, n = 6). Transplantation of Adora2b(-/-) BM into WT mice increased infarct sizes by 20 ± 3% and troponin I concentrations by 69.7 ± 17.9 ng/ml (mean ± SD, n = 6). Studies on the reperfused myocardium revealed PMNs as the dominant cell type. PMN depletion or Adora2b agonist treatment reduced infarct sizes by 30 ± 11% or 26 ± 13% (mean ± SD, n = 4); however, the combination of both did not produce additional cardioprotection. Cytokine profiling showed significantly higher cardiac tumor necrosis factor α concentrations in Adora2b(-/-) compared with WT mice (39.3 ± 5.3 vs. 7.5 ± 1.0 pg/mg protein, mean ± SD, n = 4). Pharmacologic studies on human-activated PMNs revealed an Adora2b-dependent tumor necrosis factor α release.
  
  
  CONCLUSIONS
  Adora2b signaling on BM-derived cells such as PMNs represents an endogenous cardioprotective mechanism during cardiac I-R. The authors' findings suggest that Adora2b agonist treatment during cardiac I-R reduces tumor necrosis factor α release of PMNs, thereby dampening tissue injury.
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Koeppen
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bonney
authors.forename: Megan
authors.initials: M
authors.lastname: Bonney
authors.forename: Susan
authors.initials: S
authors.lastname: Reithel
authors.forename: Cornelia
authors.initials: C
authors.lastname: Zachskorn
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Tobias
authors.initials: T
authors.lastname: Eckle
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000502:physiology; D017690:Cell Transplantation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050506:Mutant Chimeric Proteins; D017202:Myocardial Ischemia / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology; D009504:Neutrophils / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014970:Xanthines / Q000494:pharmacology*
chemical_list: C518874:1-propyl-8-(4-sulfophenyl)xanthine; D058908:Adenosine A2 Receptor Agonists; D000631:Aminopyridines; C518875:BAY 60-6583; D050506:Mutant Chimeric Proteins; D043704:Receptor, Adenosine A2B; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; D009195:Peroxidase