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

Muhammad Imtiaz Ashraf, Matthias Ebner, Christoph Wallner, Martina Haller, Sana Khalid, Hubert Schwelberger, Katarzyna Koziel, Marion Enthammer, Martin Hermann, Stephan Sickinger, Afschin Soleiman, Christina Steger, Stephanie Vallant, Robert Sucher, Gerald Brandacher, Peter Santer, Duska Dragun, Jakob Troppmair

Research output: Contribution to journalArticle

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. 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. 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.

Original languageEnglish (US)
Article number6
JournalCell Communication and Signaling
Volume12
Issue number1
DOIs
StatePublished - Jan 14 2014

Fingerprint

Cell death
Reperfusion Injury
Oxidation-Reduction
Reactive Oxygen Species
Cell Death
Reperfusion
Ischemia
Chemical activation
Tissue
Wounds and Injuries
MAP-kinase-activated kinase 2
Cardiac Myocytes
Constriction
Small Interfering RNA
Protein Isoforms
Phosphotransferases
Antioxidants
Kidney
Molecules

Keywords

  • Apoptosis
  • Ischemia/reperfusion injury (IRI)
  • Kidney
  • p38MAPK signaling
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biochemistry
  • Medicine(all)

Cite this

Ashraf, M. I., Ebner, M., Wallner, C., Haller, M., Khalid, S., Schwelberger, H., ... Troppmair, J. (2014). A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury. Cell Communication and Signaling, 12(1), [6]. https://doi.org/10.1186/1478-811X-12-6

A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury. / Ashraf, Muhammad Imtiaz; Ebner, Matthias; Wallner, Christoph; Haller, Martina; Khalid, Sana; Schwelberger, Hubert; Koziel, Katarzyna; Enthammer, Marion; Hermann, Martin; Sickinger, Stephan; Soleiman, Afschin; Steger, Christina; Vallant, Stephanie; Sucher, Robert; Brandacher, Gerald; Santer, Peter; Dragun, Duska; Troppmair, Jakob.

In: Cell Communication and Signaling, Vol. 12, No. 1, 6, 14.01.2014.

Research output: Contribution to journalArticle

Ashraf, MI, 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 2014, 'A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury', Cell Communication and Signaling, vol. 12, no. 1, 6. https://doi.org/10.1186/1478-811X-12-6
Ashraf, Muhammad Imtiaz ; Ebner, Matthias ; Wallner, Christoph ; Haller, Martina ; Khalid, Sana ; Schwelberger, Hubert ; Koziel, Katarzyna ; Enthammer, Marion ; Hermann, Martin ; Sickinger, Stephan ; Soleiman, Afschin ; Steger, Christina ; Vallant, Stephanie ; Sucher, Robert ; Brandacher, Gerald ; Santer, Peter ; Dragun, Duska ; Troppmair, Jakob. / A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury. In: Cell Communication and Signaling. 2014 ; Vol. 12, No. 1.
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AU - Ebner, Matthias

AU - Wallner, Christoph

AU - Haller, Martina

AU - Khalid, Sana

AU - Schwelberger, Hubert

AU - Koziel, Katarzyna

AU - Enthammer, Marion

AU - Hermann, Martin

AU - Sickinger, Stephan

AU - Soleiman, Afschin

AU - Steger, Christina

AU - Vallant, Stephanie

AU - Sucher, Robert

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AU - Santer, Peter

AU - Dragun, Duska

AU - Troppmair, Jakob

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