Targeted deletion of A3 adenosine receptors improves tolerance to ischemia-reperfusion injury in mouse myocardium

Abstract

A3 adenosine receptors (A3ARs) have been implicated in regulating mast cell function and in cardioprotection during ischemia-reperfusion injury. The physiological role of A3ARs is unclear due to the lack of widely available selective antagonists. Therefore, we examined mice with targeted gene deletion of the A3AR together with pharmacological studies to determine the role of A3ARs in myocardial ischemia-reperfusion injury. We evaluated the functional response to 15-min global ischemia and 30-min reperfusion in isovolumic Langendorff hearts from A3AR−/−and wild-type (A3AR+/+) mice. Loss of contractile function during ischemia was unchanged, but recovery of developed pressure in hearts after reperfusion was improved in A3AR−/− compared with wild-type hearts (80 ± 3 vs. 51 ± 3% at 30 min). Tissue viability assessed by efflux of lactate dehydrogenase was also improved in A3AR−/− hearts (4.5 ± 1 vs. 7.5 ± 1 U/g). The adenosine receptor antagonist BW-A1433 (50 μM) decreased functional recovery following ischemia in A3AR−/− but not in wild-type hearts. We also examined myocardial infarct size using an intact model with 30-min left anterior descending coronary artery occlusion and 24-h reperfusion. Infarct size was reduced by over 60% in A3AR−/− hearts. In summary, targeted deletion of the A3AR improved functional recovery and tissue viability during reperfusion following ischemia. These data suggest that activation of A3ARs contributes to myocardial injury in this setting in the rodent. Since A3ARs are thought to be present on resident mast cells in the rodent myocardium, we speculate that A3ARs may have proinflammatory actions that mediate the deleterious effects of A3AR activation during ischemia-reperfusion injury.