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

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.