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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/H2523    most recent 00612.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morrison, R. R. Articles by Hofmann, P. A. Search for Related Content PubMed PubMed Citation Articles by Morrison, R. R. Articles by Hofmann, P. A.

Targeted deletion of A_2A adenosine receptors attenuates the protective effects of myocardial postconditioning

¹Division of Critical Care Medicine, St. Jude Children's Research Hospital, Memphis and ²Department of Physiology, University of Tennessee Health Sciences Center, Memphis, Tennessee; ³Universite Libre de Bruxelles, Brussels, Belgium; and ⁴Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia

Submitted 25 May 2007 ; accepted in final form 30 July 2007

Endogenous adenosine is an important ligand trigger for the cardioprotective effects of postconditioning (POC), yet it is unclear which adenosine receptor subtype is primarily responsible. To evaluate the role of A_2A adenosine receptors in POC-induced protection, global ischemia-reperfusion was performed with and without POC in isolated wild-type (WT) and A_2A adenosine receptor knockout (A_2AKO) mouse hearts. Injury was measured in terms of postischemic functional recovery and release of cardiac troponin I (cTnI). Activation of protective signaling with POC was assessed by Akt and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation. In WT hearts, POC improved recovery of postischemic developed pressure in early (81.6 ± 6.4% of preischemic baseline vs. 37.5 ± 5.6% for non-POC WT at 1 min) and late (62.2 ± 4.2% of baseline vs. 45.5 ± 5.3% for non-POC WT at 30 min) reperfusion, reduced cTnI release by 37%, and doubled the phosphorylation of both Akt and ERK1/2. These beneficial effects of POC were blocked by treatment with the selective A_2A adenosine receptor antagonist ZM-241385 during reperfusion. Postischemic functional recovery, cTnI release, and phosphorylation of Akt and ERK1/2 were not different between non-POC WT and A_2AKO hearts. In A_2AKO hearts, POC did not improve functional recovery, reduce cTnI release, nor increase phosphorylation of Akt or ERK1/2. Thus the protective effects of POC are attenuated by both selective A_2A receptor antagonism and targeted deletion of the gene encoding A_2A adenosine receptors. These observations support the conclusion that endogenous activation of A_2A adenosine receptors is an essential trigger leading to the protective effects of POC in isolated murine hearts.

ischemia-reperfusion; cardiac troponin I; phosphorylated Akt; phosphorylated extracellular signal-regulated kinase 1/2

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