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Erythropoietin Modulates Autophagy Signaling in the Developing Rat Brain in an In Vivo Model of Oxygen-Toxicity
Department of Pediatrics I, Neonatology, University Hospital Essen, 45122 Essen, Germany
Department of Anaesthesiology and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany
Institute of Molecular Biology, University of Duisburg-Essen, 45122 Essen, Germany
Department of Neonatology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13353 Berlin, Germany
Department of Molecular Neurobiochemistry, Ruhr-University Bochum, 44780 Bochum, Germany
* Author to whom correspondence should be addressed.
Received: 19 July 2012; in revised form: 28 August 2012 / Accepted: 21 September 2012 / Published: 10 October 2012
Abstract: Autophagy is a self-degradative process that involves turnover and recycling of cytoplasmic components in healthy and diseased tissue. Autophagy has been shown to be protective at the early stages of programmed cell death but it can also promote apoptosis under certain conditions. Earlier we demonstrated that oxygen contributes to the pathogenesis of neonatal brain damage, which can be ameliorated by intervention with recombinant human erythropoietin (rhEpo). Extrinsic- and intrinsic apoptotic pathways are involved in oxygen induced neurotoxicity but the role of autophagy in this model is unclear. We analyzed the expression of autophagy activity markers in the immature rodent brain after exposure to elevated oxygen concentrations. We observed a hyperoxia-exposure dependent regulation of autophagy-related gene (Atg) proteins Atg3, 5, 12, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3), LC3A-II, and LC3B-II which are all key autophagy activity proteins. Interestingly, a single injection with rhEpo at the onset of hyperoxia counteracted these oxygen-mediated effects. Our results indicate that rhEpo generates its protective effect by modifying the key autophagy activity proteins.
Keywords: autophagy; developing brain; oxidative stress; hyperoxia; erythropoietin
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Bendix, I.; Schulze, C.; Haefen, C.; Gellhaus, A.; Endesfelder, S.; Heumann, R.; Felderhoff-Mueser, U.; Sifringer, M. Erythropoietin Modulates Autophagy Signaling in the Developing Rat Brain in an In Vivo Model of Oxygen-Toxicity. Int. J. Mol. Sci. 2012, 13, 12939-12951.
Bendix I, Schulze C, Haefen C, Gellhaus A, Endesfelder S, Heumann R, Felderhoff-Mueser U, Sifringer M. Erythropoietin Modulates Autophagy Signaling in the Developing Rat Brain in an In Vivo Model of Oxygen-Toxicity. International Journal of Molecular Sciences. 2012; 13(10):12939-12951.
Bendix, Ivo; Schulze, Corina; Haefen, Clarissa von; Gellhaus, Alexandra; Endesfelder, Stefanie; Heumann, Rolf; Felderhoff-Mueser, Ursula; Sifringer, Marco. 2012. "Erythropoietin Modulates Autophagy Signaling in the Developing Rat Brain in an In Vivo Model of Oxygen-Toxicity." Int. J. Mol. Sci. 13, no. 10: 12939-12951.