A3 adenosine receptor activation during reperfusion reduces infarct size through actions on bone marrow-derived cells

The goal of this study was to examine whether the A(3) adenosine receptor (A(3)AR) agonist Cl-IB-MECA protects against myocardial ischemia/reperfusion injury when administered at the time of reperfusion in an in vivo mouse model of infarction induced by 30 min of coronary occlusion and 24 h of reperfusion. Treating B6 wild-type with Cl-IB-MECA during the reperfusion phase (100 mu g/kg i.v. bolus +0.3 mu g/kg/min subcutaneously via implantation of Alzet mini-osmotic pumps) reduced myocardial infarct size similar to 37% from 50.1 +/- 2.5% in vehicle-treated mice to 31.6 +/- 2.8% in Cl-IB-MECA-treated mice, and significantly reduced the number of leukocytes that infiltrated into the ischemic-reperfused myocardium. Cl-IB-MECA did not reduce infarct size or limit leukocyte accumulation in studies using 86 congenic A(3)AR gene "knock-out" mice or in chimeric mice lacking the expression of A(3)ARs in bone marrow (BM)-derived cells. Subsequent mechanistic studies demonstrated that Cl-IB-MECA inhibited migration of mouse neutrophils isolated from BM towards the chemotactic substance c5a in trans-well migration assays, and inhibited leukocyte migration into the peritoneal cavity in a mouse model of thioglycollate-induced peritonitis. We conclude that treating with the A(3)AR agonist Cl-IB-MECA at the time of reperfusion provides effective protection from ischemia/reperfusion injury in the heart through activation of the A(3)AR expressed in BM-derived cells, potentially by suppressing the robust inflammatory reaction that occurs during reperfusion and neutrophil-mediated tissue injury. (C) 2010 Elsevier Ltd. All rights reserved.