title: The adenosine A₂A receptor - myocardial protectant and coronary target in endotoxemia.
abstract: BACKGROUND
  Cardiac injury and dysfunction are contributors to disease progression and mortality in sepsis. This study evaluated the cardiovascular role of intrinsic A₂A adenosine receptor (A₂AAR) activity during lipopolysaccharide (LPS)-induced inflammation.
  
  
  METHODS
  We assessed the impact of 24 h of LPS challenge (20 mg/kg, IP) on cardiac injury, coronary function and inflammatory mediator levels in Wild-Type (WT) mice and mice lacking functional A₂AARs (A₂AAR KO).
  
  
  RESULTS
  Cardiac injury was evident in LPS-treated WTs, with ~7-fold elevation in serum cardiac troponin I (cTnI), and significant ventricular and coronary dysfunction. Absence of A₂AARs increased LPS-provoked cTnI release at 24 h by 3-fold without additional demise of contraction function. Importantly, A₂AAR deletion per se emulated detrimental effects of LPS on coronary function, and LPS was without effect in coronary vessels lacking A₂AARs. Effects of A₂AAR KO were independent of major shifts in circulating C-reactive protein (CRP) and haptoglobin. Cytokine responses were largely insensitive to A₂AAR deletion; substantial LPS-induced elevations (up to 100-fold) in IFN-γ and IL-10 were unaltered in A₂AAR KO mice, as were levels of IL-4 and TNF-α. However, late elevations in IL-2 and IL-5 were differentially modulated by A₂AAR KO (IL-2 reduced, IL-5 increased). Data demonstrate that in the context of LPS-triggered cardiac and coronary injury, A₂AAR activity protects myocardial viability without modifying contractile dysfunction, and selectively modulates cytokine (IL-2, IL-5) release. A₂AARs also appear to be targeted by LPS in the coronary vasculature.
  
  
  CONCLUSIONS
  These experimental data suggest that preservation of A₂AAR functionality might provide therapeutic benefit in human sepsis.
authors.affiliation: Heart Foundation Research Center, Griffith University, Southport QLD, Australia. mrei@unimelb.edu.au
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Reichelt
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Ashton
authors.forename: Xing Lin
authors.initials: XL
authors.lastname: Tan
authors.forename: S Jamal
authors.initials: SJ
authors.lastname: Mustafa
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.forename: Lea M D
authors.initials: LM
authors.lastname: Delbridge
authors.forename: Polly A
authors.initials: PA
authors.lastname: Hofmann
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
authors.forename: R Ray
authors.initials: RR
authors.lastname: Morrison
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D003327:Coronary Disease / Q000235:genetics / Q000378:metabolism*; D019446:Endotoxemia / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology; D043683:Receptors, Adenosine A2 / Q000172:deficiency* / Q000235:genetics
chemical_list: D002316:Cardiotonic Agents; D008070:Lipopolysaccharides; D043683:Receptors, Adenosine A2