TY - JOUR
T1 - A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury
AU - Ashraf, Muhammad Imtiaz
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
AU - Brandacher, Gerald
AU - Santer, Peter
AU - Dragun, Duska
AU - Troppmair, Jakob
N1 - Funding Information:
This work has been supported by grants from the Jubiläumsfond der Österreichischen Nationalbank (OeNB) project Nr. 13273, Austrian Science Foundation (FWF), MCBO, ZFW011010-08, Austrian Federal Ministries BMVIT/ BMWFJ (via FFG) and the Tiroler Zukunftsstiftung/Standortagentur Tirol (SAT), the Österreichische Krebshilfe Tirol, the Higher Education Commission (HEC) Pakistan (support of MIA) and made possible through all the dedicated lab members. The support by Mrs. Ruth Baldauf in the preparation of the manuscript is greatly appreciated. We are grateful to our colleagues Prof. W. C. Claycomb (Departments of Biochemistry and Molecular Biology, Louisiana State University Medical Center, New Orleans, LA) for the gift of HL-1 cells and Prof. Matthias Gaestel (Hannover, Germany) for providing us with MK2-deficient murine fibroblasts. We thank PD Florian Fuller MD, Uwe Hoff MD and Lyubov Chaykovska (Laboratoy of Duska Dragun) for technical support. PD Dr. Andrey Kozlov is acknowledged for his input in ROS measurement. Sincere thanks go to Prof. Raimund Margreiter, founder of the DSL and great supporter of its activities. We thank Profs. Wolfgang Doppler (Biocenter, IMU), and Alexander Rosenkranz (Graz Medical University, Austria) for their input as members of the thesis committee for MIA.
PY - 2014/1/14
Y1 - 2014/1/14
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Ischemia/reperfusion injury (IRI)
KW - Kidney
KW - Reactive oxygen species (ROS)
KW - p38MAPK signaling
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U2 - 10.1186/1478-811X-12-6
DO - 10.1186/1478-811X-12-6
M3 - Article
C2 - 24423080
AN - SCOPUS:84892382971
SN - 1478-811X
VL - 12
JO - Cell Communication and Signaling
JF - Cell Communication and Signaling
IS - 1
M1 - 6
ER -