title: Extracellular NAADP affords cardioprotection against ischemia and reperfusion injury and involves the P2Y11-like receptor.
abstract: OBJECTIVE
  Extracellular nucleotides may play important regulatory roles within the cardiovascular system and notably in cardioprotection. We aimed to look for a possible pharmacological preconditioning effect of extracellular NAADP ([NAADP]e) against ischemia/reperfusion injury. [NAADP]e has been recently reported to be a full agonist of the P2Y11 receptor. Therefore, we characterized the involvement of the P2Y11-like receptor in mediating ischemic/reperfusion tolerance induced by [NAADP]e.
  
  
  METHODS
  The cardioprotective effects of [NAADP]e were evaluated in a model of ischemia/reperfusion carried out on Langendorff perfused rat hearts. This model was also instrumented with a microdialysis probe. Furthermore, using isolated cardiomyocytes, we assessed cAMP, inositol phosphate accumulation and prosurvival protein kinases activation induced by [NAADP]e pretreatement.
  
  
  RESULTS
  Pretreatment with 1μM [NAADP]e induced cardioprotective effects with regards to functional recovery, necrosis and arrhythmogenesis (p<0.05). These effects were completely suppressed with NF157, an antagonist of the P2Y11 receptor. Moreover, global ischemia induced a time-dependent increase in interstitial concentration of adenosine, NAADP and UTP. In cardiomyocyte cultures, NF157 suppressed cAMP and inositol phosphate accumulation induced by [NAADP]e. [NAADP]e induced phosphorylation of ERK 1/2, AKT and its downstream target GSK-3β (p<0.05). These activations were also suppressed by NF157.
  
  
  CONCLUSIONS
  Evidence suggests that NAADP signalling at the P2Y11-like receptor affords significant cardioprotection against ischemia/reperfusion injury. Besides adenosine and UTP, microdialysis study supports a potential endogenous role of [NAADP]e.
authors.affiliation: Department of Pharmacology, EA 3801, SFR CAP-santé, Reims University Hospital, 51 rue Cognacq-Jay, 51095 Reims Cedex, France. zoubir.djerada@univ-reims.fr
authors.forename: Zoubir
authors.initials: Z
authors.lastname: Djerada
authors.forename: Hélène
authors.initials: H
authors.lastname: Peyret
authors.forename: Sylvain
authors.initials: S
authors.lastname: Dukic
authors.forename: Hervé
authors.initials: H
authors.lastname: Millart
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D015153:Blotting, Western; D002316:Cardiotonic Agents; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D007295:Inositol Phosphates / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009249:NADP / Q000031:analogs & derivatives* / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology*
chemical_list: D002316:Cardiotonic Agents; D007295:Inositol Phosphates; C109734:P2RY11 protein, human; D018048:Receptors, Purinergic P2; D009249:NADP; C024376:NAADP; D000242:Cyclic AMP; D011494:Protein Kinases