Mechanisms of cardiac protection with overexpression of A₁ adenosine receptors

Myocardial damage from ischemia/reperfusion injury can be minimized through endogenous protective mechanisms, including activation of A₁ adenosine receptors. Transgenic mice with cardiac-specific A₁ adenosine receptor overexpression (A₁AR Trans) have demonstrated functional and metabolic tolerance to in vitro and in vivo myocardial ischemia/reperfusion injury. The purpose of this investigation is to examine the role of p38 MAP kinase in A₁ receptor-mediated cardioprotection. Activation of p38 MAPK by A₁ adenosine receptor stimulation was evaluated in neonatal rat cardiomyocytes subjected to simulated ischemia. A₁ activation by cyclopentyladenosine decreased cell death and simultaneously enhanced p38 phosphorylation by simulated ischemia. The role of p38 MAP kinase activation in cardioprotection with A₁ adenosine receptor overexpression was evaluated in isolated perfused hearts from A₁AR Trans mice subjected to 20 min ischemia and 30 min reperfusion. Inhibition of p38 MAPK activity with 10 μM SB-203580 prior to ischemia and during reperfusion decreased postischemic total functional recovery in A₁AR Trans hearts from 54 ± 1 to 27±7% of maximal and increased final EDP from 10±3 mmHg to 34±8 mmHg. A₁ adenosine receptor-mediated activation of p38 MAP kinase in cardiomyocytes is involved in the protection of cells from ischemic death. Tolerance to ischemic injury by A₁ receptor overexpression is dependent upon activation of p38 MAPK. These findings suggest that adenosine A₁ mediated cardioprotection in transgenic mice involves activation of the p38 MAP kinase cascade.