Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.
Bottom Line: In this study, we found that disturbed flow activated anti-oxidative reactions via up-regulating heme oxygenase 1 (HO-1) in an X-box-binding protein 1 (XBP1) and histone deacetylase 3 (HDAC3)-dependent manner.Knockdown of HDAC3 ablated XBP1u-mediated effects.Thus, we demonstrate that XBP1u and HDAC3 exert a protective effect on disturbed flow-induced oxidative stress via up-regulation of mTORC2-dependent Akt1 phosphorylation and Nrf2-mediated HO-1 expression.
Affiliation: From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.Show MeSH
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Mentions: HDAC3 has been demonstrated to protect cells from oxidative stress (19, 25). To assess whether up-regulation of XBP1u has a similar protective effect, arterial segments were isolated from Tie2-LacZ/ApoE−/− mice and infected with Ad- or Ad-XBP1u viruses followed by 50 μmol/liter H2O2 challenge. In these mice, the β-galactosidase is selectively expressed in endothelial cells and some progenitor cells driven by the Tie2 promoter. X-gal staining reveals the endothelium. Overexpression of XBP1u significantly reduced H2O2-induced EC loss from the vessel wall (Fig. 2A), which was further confirmed by in vitro experiments challenging HUVECs with 50 μmol/liter H2O2 (Fig. 2B). In contrast, knockdown of XBP1 via shRNA lentiviral infection slightly increased the basal level of cell apoptosis but significantly augmented H2O2-induced HUVECs apoptosis even at a low concentration (20 μmol/liter) (Fig. 2C). Wild type and XBP1 (XBP1−/−) embryonic fibroblasts were isolated from XBP1+/− cross-bred mouse embryonic day 8.5 embryos and verified by PCR (Fig. 2D). Spontaneously apoptotic cells were higher in XBP1 cells than that in wild type cells (4% versus 1%), which dramatically increased after 20 μmol/liter H2O2 challenge (35% versus 2.5%, Fig. 2E). These results suggest that XBP1u is essential for EC survival especially under oxidative stress.
Affiliation: From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.