Steinbrenner Holger, Alili Lirija, Bilgic Esra, Sies Helmut, Brenneisen Peter
Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
Free Radic Biol Med. 2006 May 1;40(9):1513-23. doi: 10.1016/j.freeradbiomed.2005.12.022. Epub 2006 Jan 13.
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.
硒蛋白P（SeP）是一种高度糖基化、富含硒的血浆蛋白。除了作为硒载体蛋白的作用外，SeP还被认为具有抗氧化功能。星形胶质细胞可清除大脑中的活性氧，被描述为SeP的潜在靶细胞。我们研究了SeP在人星形胶质细胞中的表达及其在保护这些细胞免受叔丁基过氧化氢（t-BHP）诱导的氧化损伤中的作用。我们发现原代人星形胶质细胞和人星形细胞瘤细胞系MOG-G-CCM表达的SeP是一种未糖基化的蛋白，且不分泌。星形胶质细胞中SeP的表达是组成型的。用肝细胞来源的SeP对星形胶质细胞进行预孵育，可模拟低分子量硒化合物（如亚硒酸钠或硒代蛋氨酸）对氧化损伤的保护作用，使星形胶质细胞免受t-BHP诱导的细胞毒性。向星形胶质细胞补充硒可通过增加硒酶胞质谷胱甘肽过氧化物酶（cGPx）的表达和活性来对抗氧化应激。此外，通过小干扰RNA特异性下调SeP表达会降低人星形胶质细胞的活力，并使它们更容易受到t-BHP诱导的细胞毒性。我们的结果表明，在缺硒的星形胶质细胞中，组成型表达的SeP具有抗氧化活性，而在硒供应充足时，cGPx发挥增强的抗氧化应激保护作用。
