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

Cell Communication and Signaling

Research

Duska Dragun¹  Matthias Ebner²  Sana Khalid²  Katarzyna Koziel²  Stephanie Vallant²  Jakob Troppmair²  Muhammad Imtiaz Ashraf²  Christoph Wallner²  Robert Sucher²  Martina Haller²  Stephan Sickinger²  Marion Enthammer²  Peter Santer³  Gerald Brandacher⁴  Christina Steger⁵  Martin Hermann⁶  Hubert Schwelberger⁷  Afschin Soleiman⁸ 

[1] Clinic for Nephrology and Intensive Care Medicine, Charité, Augustenburger Platz 1, 13353, Berlin, Germany;Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University (IMU), Innrain 66, 6020, Innsbruck, Austria;Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University (IMU), Innrain 66, 6020, Innsbruck, Austria;Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University (IMU), Anichstraße 35, 6020, Innsbruck, Austria;Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;Daniel Swarovski Research Laboratory, Department of Visceral, Transplant- and Thoracic Surgery, Innsbruck Medical University (IMU), Innrain 66, 6020, Innsbruck, Austria;Reconstructive Transplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA;Department for Pathology, Innsbruck Medical University, Innsbruck Medical University (IMU), Anichstraße 35, 6020, Innsbruck, Austria;Department of Anesthesiology and Critical Care Medicine, Innsbruck Medical University (IMU), Anichstraße 35, 6020, Innsbruck, Austria;Department of Pediatrics II, Innsbruck Medical University, Anichstraße 35, 6020, Innsbruck, Austria;Molecular Biology Laboratory, Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University (IMU), Schöpfstraße 41, 6020, Innsbruck, Austria;Soleiman Pathologie, Kugelanger 12a, 8060 Hall in Tirol, Austria;

关键词: p38MAPK signaling;    Ischemia/reperfusion injury (IRI);    Reactive oxygen species (ROS);    Apoptosis;    Kidney;   

DOI  :  10.1186/1478-811X-12-6

 received in 2013-09-10, accepted in 2014-01-04,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundMany 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.ResultsHere 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.ConclusionsThese 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.

【 授权许可】

Unknown   
© Ashraf et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.