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1 Surgery, University of Kentucky, Lexington, KY, USA
* To whom correspondence should be addressed. E-mail: ccrof2{at}uky.edu.
Although acute adenosine preconditioning (PC) is well established, the signaling pathways mediating this cardioprotection remain unclear. Since adenosine receptor agonists activate p38 MAPK and this kinase has been implicated in ischemic/pharmacological PC, the purpose of this study was to determine the role of p38 MAPK in acute adenosine receptor PC. The role of p38 MAPK activation in discrete subcellular compartments during ischemia/reperfusion was also determined. The following groups were used in an in vivo rat ischemia/reperfusion model: 1) Control (10% DMSO, i.v.), 2) A1/2a adenosine receptor agonist AMP579 (50 µg/kg, i.v.), 3) AMP579 + the A1 receptor antagonist DPCPX (100 µg/kg, i.v.), 4) AMP579 + the p38 MAPK inhibitor SB203580 (1mg/kg, i.v.), and 5) SB203580 alone. P38 MAPK activation was measured by western blot analysis in cytosolic, mitochondrial, membrane, and nuclear/myofilament fractions obtained from hearts at pre-ischemic, ischemic, and reperfusion time points. A significant reduction in infarct size was observed with AMP579 PC, an effect blocked by DPCPX or SB203580 pretreatment. AMP579 treatment was associated with a significant increase in p38 MAPK activation in the nuclear/myofilament fraction prior to ischemia, while no activation of this kinase occurred during ischemia or reperfusion. By contrast, p38 MAPK was activated in the mitochondrial fraction by ischemia and the cytosolic, mitochondrial, and membrane fractions by reperfusion in the control. SB203580 blocked the AMP579-induced increase in the phosphorylation of the downstream p38 substrate ATF-2. These results suggest a role for p38 MAPK activation in discrete subcellular compartments in acute adenosine A1 receptor PC.
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