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Human-specific induction of glutathione peroxidase-3 by proteasome inhibition in cardiovascular cells

2009; Elsevier BV; Volume: 47; Issue: 11 Linguagem: Inglês

10.1016/j.freeradbiomed.2009.09.017

1873-4596

Kera Westphal, Verena Stangl, Michael Fähling, Henryk Dreger, Andrea Weller, Gert Baumann, Karl Stangl, Silke Meiners,

Redox biology and oxidative stress

Glutathione peroxidase-3 (GPx-3) is a key antioxidant enzyme in the plasma. GPx-3 was previously identified as the major antioxidative enzyme that was induced upon nontoxic proteasome inhibition in endothelial cells. Here, we investigated the determinants of the proteasome inhibitor-induced expression of GPx-3. Nontoxic proteasome inhibition massively upregulates GPx-3 RNA and protein in human umbilical cord vein cells within 24 h. Surprisingly, induction of GPx-3 was species-specific for human cells. The exponential upregulation of GPx-3 is mediated by transcriptional activation of the human GPx-3 promoter and, in addition, stabilization of GPx-3 mRNA: in reporter gene assays with full-length and deleted variants of the human GPx-3 promoter we identified a putative antioxidative response element (ARE) as essential and also sufficient for transcriptional activation of GPx-3 by proteasome inhibition. However, the ARE-specific antioxidative transcription factor Nrf2 is not involved in the activation of GPx-3. UV-crosslinking using the 3′UTR of GPx-3 revealed an altered protein binding pattern in the presence of proteasome inhibitors, thus indicating regulation of mRNA stability of human GPx-3. As GPx-3 is secreted into the plasma, our data point toward a borderline defense mechanism of endothelial cell-derived GPx-3 to protect the vasculature from oxidative stress.