A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury
- PDF / 1,477,304 Bytes
- 13 Pages / 595.28 x 793.7 pts Page_size
- 63 Downloads / 180 Views
RESEARCH
Open Access
A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury Muhammad Imtiaz Ashraf1, Matthias Ebner1, Christoph Wallner1, Martina Haller1, Sana Khalid1, Hubert Schwelberger2, Katarzyna Koziel1, Marion Enthammer1, Martin Hermann3,4, Stephan Sickinger1, Afschin Soleiman5, Christina Steger6, Stephanie Vallant1, Robert Sucher1, Gerald Brandacher1,8, Peter Santer1,3,9, Duska Dragun7 and Jakob Troppmair1*
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. Keywords: p38MAPK signaling, Ischemia/reperfusion injury (IRI), Reactive oxygen species (ROS), Apoptosis, Kidney
Background Ischemia/reperfusion injury (IRI) contributes to morbidity and mortality in a wide range of pathologies including acute coronary syndrome, stroke, acute kidney injury, sickle cell disease and is particularly unavoidable during solid organ transplantation [1]. ROS are central to the initiation and progression of damage to organs throughout * Correspondence: [email protected] 1 Daniel Swarovski Research Laboratory, Department of Visceral, Transplantand Thoracic Surgery, Innsbruck Medical University (IMU), Innrain 66, 6020 Innsbruck, Austria Full list of author information is available at the end of the article
ischemia/reperfusion (IR). In particular, during the early phase of reperfusion excessive amounts of ROS are produced, which through direct da
Data Loading...
