Role of phasic dynamism of p38 mitogen-activated protein kinase activationin ischemic preconditioning of the canine heart

Although ischemic stress, including ischemic preconditioning (IP), activate s p38 mitogen-activated protein kinase (MAPK), the relationship between p38 MAPK activation and the underlying cellular mechanisms of cardioprotection by IP is not verified in vivo. We examined the effects of the selective p3 8 MAPK inhibition on the cardioprotective effect of IP in the open-chest do gs. The coronary artery was occluded 4 times for 5 minutes, separated by 5 minutes of reperfusion (IP) followed by 90 minutes of occlusion and 6 hours of reperfusion. We infused SB203580 into the coronary artery during IP and 1 hour of reperfusion, during IP alone, and during sustained ischemia in t he IP group. p38 MAPK activity markedly increased during IP but did not add itionally increase at the onset of ischemia and was even attenuated at 15 m inutes of sustained ischemia, and heat-shock protein (HSP) 27 was phosphory lated and translocated from cytosol to myofibril or nucleus without affecti ng total protein level at the onset of ischemia compared with the control g roup. SB203580 treatment (1 mu mol/L) only during LP blunted the infarct si ze limitation by IP (37.3+/-6.3% versus 7.4+/-2.15 in the IP group, P<0.01) and attenuated either phosphorylation or translocation of HSP27 during IP. Although the SB203580 treatment throughout the preischemic and postischemi c periods had no significant effect on infarct size (33.3+/-9.4%) in this m odel, treatment with SB203580 only during ischemia partially mimicked the i nfarct size limitation by IP (26.8+/-3.5%). Thus, transient p38 MAPK activa tion during ischemic preconditioning mainly mediates the cardioprotection f ollowed by HSP27 phosphorylation and translocation in vivo in the canine he art.