alexa The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes


Journal of Anesthesia & Clinical Research


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Activation of protein kinase C (PKC) and more recently mitogen-activated protein kinases (MAPKs) have been associated with the cardioprotective effect of ischemic preconditioning. We examined the interplay between these kinases in a characterized model of ischemic preconditioning in cultured rat neonatal ventricular cardiocytes where ectopic expression of active PKC-δ results in protection. Two members of the MAPK family, p38 and p42/44, were activated transiently during preconditioning by brief simulated ischemia/reoxygenation. Overexpression of active PKC-δ, rather than augmenting, completely abolished this activation. We therefore determined whether a similar process occurred during lethal prolonged simulated ischemia. In contrast to ischemia, brief, lethal-simulated ischemia activated only p38 (2.8±0.45 vs. basal, P<0.01), which was attenuated by expression of active PKC-δ or by preconditioning (0.48±0.1 vs. ischemia, P<0.01). To determine whether reduced p38 activation was the cause or an effect of protection, we used SB203580, a p38 inhibitor. SB203580 reduced ischemic injury (CK release 38.0±3.1%, LDH release 77.3±4.0%, and MTT bioreduction 127.1±4.8% of control, n=20, P<0.05). To determine whether p38 activation was isoform selective, myocytes were infected with adenoviruses encoding wild-type p38α or p38β. Transfected p38α and β show differential activation (P<0.001) during sustained simulated ischemia, with p38α remaining activated (1.48±0.36 vs. basal) but p38β deactivated (0.36±0.1 vs. basal, P<0.01). Prior preconditioning prevented the activation of p38α (0.65±0.11 vs. ischemia, P<0.05). Moreover, cells expressing a dominant negative p38α, which prevented ischemic p38 activation, were resistant to lethal simulated ischemia (CK release 82.9±3.9% and MTT bioreduction 130.2±6.5% of control, n=8, P<0.05). Thus, inhibition of p38α activation during ischemia reduces injury and may contribute to preconditioning-induced cardioprotection in this model.—Saurin, A. T., Martin, J. L., Heads, R. J., Foley, C., Mockridge, J. W., Wright, M. J., Wang, Y., Marber, M. S. The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes.

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This article was published in FASEB Journal and referenced in Journal of Anesthesia & Clinical Research

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