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

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.;Troppmair,J.;
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. Results: Here we identified p38MAPK alpha as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPK alpha 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. 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.
Cell Communication and Signaling 2014 12:
Tags: p38mapk signaling; ischemia/reperfusion injury (iri); reactive oxygen species (ros); apoptosis; kidney; gelatinase-associated lipocalin; acute-renal-failure; acute kidney injury; nf-kappa-b; ischemia-reperfusion; p38 mapk; oxidative stress; in-vitro; myocardial-ischemia; apoptosis;
PubMed: 24423080
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