Methionine sulfoxide reductase A protects neuronal cells against brief hypoxia/reoxygenation
- Olena Yermolaieva*,
- Rong Xu†,
- Carrie Schinstock‡,
- Nathan Brot§,
- Herbert Weissbach¶,
- Stefan H. Heinemann∥, and
- Toshinori Hoshi†,**
- *Department of Internal Medicine, ‡Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242; §Hospital for Special Surgery, Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021; ¶Center for Molecular Biology and Biotechnology, Florida Atlantic University, Boca Raton, FL 33431; ∥Molecular and Cellular Biophysics, Medical Faculty of the Friedrich Schiller University Jena, Drackendorfer Strasse 1, D-07747 Jena, Germany; and †Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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Contributed by Herbert Weissbach, December 16, 2003
Abstract
Hypoxia/reoxygenation induces cellular injury by promoting oxidative stress. Reversible oxidation of methionine in proteins involving the enzyme peptide methionine sulfoxide reductase type A (MSRA) is postulated to serve a general antioxidant role. Therefore, we examined whether overexpression of MSRA protected cells from hypoxia/reoxygenation injury. Brief hypoxia increased the intracellular reactive oxygen species (ROS) level in PC12 cells and promoted apoptotic cell death. Adenovirus-mediated overexpression of MSRA significantly diminished the hypoxia-induced increase in ROS and facilitated cell survival. Measurements of the membrane potentials of intact mitochondria in PC12 cells and of isolated rat liver mitochondria showed that hypoxia induced depolarization of the mitochondrial membrane. The results demonstrate that MSRA plays a protective role against hypoxia/reoxygenation-induced cell injury and suggest the therapeutic potential of MSRA in ischemic heart and brain disease.
Footnotes
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↵ ** To whom correspondence should be addressed at: Department of Physiology, University of Pennsylvania, Richards D100, 3700 Hamilton Walk, Philadelphia, PA 19104. E-mail: hoshi{at}hoshi.org.
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Abbreviations: met-O, methionine sulfoxide; MSRA, methionine sulfoxide reductase A; MSRB, methionine sulfoxide reductase B; bMSRA, bovine MSRA; EGFP, enhanced green fluorescent protein; PI, propidium iodide; ROS, reactive oxygen species; DHR, dihydrorhodamine; JC-1, 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine; TEMPOL, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone.
- Copyright © 2004, The National Academy of Sciences
