Ischemic Preconditioning Activates MAPKAPK2 in the Isolated Rabbit Heart

Abstract

Abstract-Recent studies suggest that p38 mitogen-activated protein kinase (MAPK) may be involved in ischemic preconditioning (PC). To further test this possibility, the regulation of MAPK-activated protein kinase 2 (MAPKAPK2), a kinase immediately downstream from p38 MAPK, and the activity of c-Jun NH 2 -terminal kinase (JNK), a second MAPK, were examined in preconditioned hearts. Isolated, perfused rabbit hearts were subjected to 20 to 30 minutes of global ischemia. Ventricular biopsies before treatment and after 20 minutes of ischemia were homogenized, and the activities of MAPKAPK2 and JNK were evaluated. For the MAPKAPK2 experiments, 7 groups were studied, as follows: control hearts; preconditioned hearts; hearts treated with 500 nmol/L R(-) N 6 -(2-phenylisopropyl) adenosine (PIA), an A 1 -adenosine receptor agonist; preconditioned hearts pretreated with 100 mol/L 8-(p-sulfophenyl) theophylline (SPT), an adenosine receptor antagonist; preconditioned hearts also treated with SB 203580, a potent inhibitor of p38 MAPK activation; hearts treated with 50 ng/mL anisomycin (a p38 MAPK/JNK activator); and hearts treated with both anisomycin (50 ng/mL) and the tyrosine kinase inhibitor genistein (50 mol/L). MAPKAPK2 activity was not altered in control hearts after 20 minutes of global ischemia. By contrast, there was a 3.8-fold increase in activity during ischemia in preconditioned hearts. Activation of MAPKAPK2 in preconditioned hearts was blocked by both SPT and SB 203580. MAPKAPK2 activity during ischemia increased 3.5-fold and 3.3-fold in hearts pretreated with PIA or anisomycin, respectively. MAPKAPK2 activation during ischemia in hearts pretreated with anisomycin was blocked by genistein. In separate hearts, anisomycin mimicked the anti-infarct effect of PC, and that protection was abolished by genistein. JNK activity was measured in control and preconditioned hearts. There was a comparable, modest decline in activity during 30 minutes of global ischemia in both groups. As a positive control, a third group of hearts was treated with anisomycin before global ischemia, and in these, JNK activity increased by 290% above baseline. These results confirm that the p38 MAPK/MAPKAPK2 pathway is activated during ischemia only if the heart is in a preconditioned state. These data further support p38 MAPK as an important signaling component in ischemic PC. (Circ Res. 2000;86:144-151.)

Activation of p38 mitogen-activated protein kinase abolishes insulin-mediated myocardial protection against ischemia-reperfusion injury

“…In the current study, we also observed a sevenfold increase in JNK phosphorylation following ischemia-reperfusion. This increase in JNK phosphorylation appears to be mediated by reperfusion and not by ischemia, as a modest decline in JNK activity was observed after 30 min of global ischemia in rat hearts (27). Moreover, ischemia per se for 30 or 45 min failed to activate JNK, but reperfusion was associated with a gradual activation of JNK (35).…”

“…In rat hearts subjected to 20 min of global ischemia, MAPK-activated protein kinase-2 (MAPKAPK2), a kinase immediately downstream from p38 MAPK, activity did not change (27). In rabbit or canine models, ischemia alone caused only a moderate but transient increase in p38 MAPK activity whereas ischemia followed by reperfusion caused a persistent elevation in p38 MAPK activity with maximal activation being reached 10 -15 min after reperfusion (22,35).…”

“…Recent evidence suggests that p38 MAPK plays a major role in the myocardial ischemia-reperfusion injury as that its targeted inhibition reduces the cardiac injury and cell death following ischemia-reperfusion in vivo (14,18,22). On the other hand, prior activation of this kinase, similar to recurrent, short-duration ischemia, preconditions the myocardium against subsequent ischemia-reperfusion injury (20,27,37).…”

Efeitos da N-acetilcisteína no precondicionamento isquêmico: estudo em corações isolados de ratos

“…Since the description of IP by Murry et al [2] in 1986, many researchers have attempt to disclose the mechanisms and directions of this phenomenon [3][4][5][6][7][8][9][10]. If the IP is considered the most powerful known natural form of cardioprotection in experimental research [3], why not use this powerful protective mechanism in heart surgery?…”

“…Nakano et al [7] showed that the translocation of PKC is related to activation of mitoK + ATP channel through the stimulation of kinases positioned just below the mitogenic-activated protein kinase p38 (MAPK). The regulation of mitochondrial volume and transport of electrons are the main mechanisms responsible CO 2 ).…”