A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury

Ashraf, M. I. et al. (2014) A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury. Cell Communication and Signaling, 12(1), p. 6. (doi: 10.1186/1478-811X-12-6)

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Publisher's URL: http://dx.doi.org/10.1186/1478-811X-12-6

Abstract

Background Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects.<p></p> Results Here we identified p38MAPKα as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKα signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death.<p></p> Conclusions These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.<p></p>

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Haller, Ms Martina
Authors: Ashraf, M. I., Ebner, M., Wallner, C., Haller, M., Khalid, S., Schwelberger, H., Koziel, K., Enthammer, M., Hermann, M., Sickinger, S., Soleiman, A., Steger, C., Vallant, S., Sucher, R., Brandacher, G., Santer, P., Dragun, D., and Troppmair, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Communication and Signaling
Publisher:BioMed Central
ISSN:1478-811X
ISSN (Online):1478-811X
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Cell Communication and Signaling 12(1):6
Publisher Policy:Reproduced under a Creative Commons License

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