title: A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury.
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.
authors.forename: Muhammad Imtiaz
authors.initials: MI
authors.lastname: Ashraf
authors.forename: Matthias
authors.initials: M
authors.lastname: Ebner
authors.forename: Christoph
authors.initials: C
authors.lastname: Wallner
authors.forename: Martina
authors.initials: M
authors.lastname: Haller
authors.forename: Sana
authors.initials: S
authors.lastname: Khalid
authors.forename: Hubert
authors.initials: H
authors.lastname: Schwelberger
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Koziel
authors.forename: Marion
authors.initials: M
authors.lastname: Enthammer
authors.forename: Martin
authors.initials: M
authors.lastname: Hermann
authors.forename: Stephan
authors.initials: S
authors.lastname: Sickinger
authors.forename: Afschin
authors.initials: A
authors.lastname: Soleiman
authors.forename: Christina
authors.initials: C
authors.lastname: Steger
authors.forename: Stephanie
authors.initials: S
authors.lastname: Vallant
authors.forename: Robert
authors.initials: R
authors.lastname: Sucher
authors.forename: Gerald
authors.initials: G
authors.lastname: Brandacher
authors.forename: Peter
authors.initials: P
authors.lastname: Santer
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
authors.affiliation: Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University (IMU), Innrain 66, 6020 Innsbruck, Austria. jakob.troppmair@i-med.ac.at.
authors.forename: Jakob
authors.initials: J
authors.lastname: Troppmair
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D048308:Mitogen-Activated Protein Kinase 14; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2