Involvement of selenoprotein P in protection of human astrocytes from oxidative damage.
Selenoprotein P (SeP) is a highly glycosylated, selenium-rich plasma protein. Aside from its role as selenium carrier protein, an antioxidative function of SeP has been suggested. Astrocytes, which detoxify reactive oxygen species in the brain, were described as potential target cells of SeP. We investigated the expression of SeP in human astrocytes and its involvement in the protection of these cells against tert-butyl hydroperoxide (t-BHP)-induced oxidative damage. We show that primary human astrocytes and the human astrocytoma cell line MOG-G-CCM express SeP as an unglycosylated protein, which is not secreted. SeP expression in astrocytes is constitutive. Preincubation of astrocytes with hepatocyte-derived SeP mimicks the protective effect of low-molecular-weight selenocompounds such as sodium selenite or selenomethionine against oxidative damage, shielding astrocytes from t-BHP-induced cytotoxicity. Selenium supplementation of astrocytes counteracts oxidative stress via an increase in expression and activity of the selenoenzyme cytosolic glutathione peroxidase (cGPx). Furthermore, specific downregulation of SeP expression by small interfering RNA decreases cell viability of human astrocytes and makes them more susceptible to t-BHP-induced cytotoxicity. Our results implicate an antioxidant activity of constitutively expressed SeP in selenium-deficient astrocytes, while during adequate selenium supply the enhanced protection against oxidative stress is exerted by cGPx.
Steinbrenner
Holger
H
Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
Alili
Lirija
L
Bilgic
Esra
E
Sies
Helmut
H
Brenneisen
Peter
P
D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012643:Selenium / Q000494:pharmacology; D051149:Selenoprotein P / Q000494:pharmacology*; D014162:Transfection; D020122:tert-Butylhydroperoxide / Q000633:toxicity
D000975:Antioxidants; D034741:RNA, Small Interfering; D051149:Selenoprotein P; D020122:tert-Butylhydroperoxide; D005979:Glutathione Peroxidase; D012643:Selenium