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: The degradation of heme produces biliverdin, ion, and carbon monoxide, in which HO-1 plays a rate-limiting role (4). It has been reported that HO-1 protects human ECs and vascular SMCs survival under H2O2 challenge (26, 27). Therefore, we wondered whether the increase of XBP1u-induced cell survival under H2O2 challenge was due to HO-1. To test this, the HO-1 inhibitor, Tin protoporphyrin IX (28), was included in H2O2 challenge experiments. Indeed, the presence of Tin protoporphyrin IX abolished XBP1u-mediated cell survival (Fig. 3A), suggesting that XBP1u promotes EC survival under oxidative stress via HO-1. Further experiments revealed that the overexpression of either XBP1u or HDAC3 up-regulated HMOX-1 gene expression at the mRNA (Fig. 3B) and protein (Fig. 3C) levels. The mRNA level of the HMOX-1 upstream transcription factor Nrf2 (29) remained unchanged (Fig. 3B), but the protein level was significantly up-regulated by XBP1u or HDAC3 (Fig. 3C), which might be through post-translational stabilization (30). Knockdown of Nrf2 by siRNA abolished Ad-XBP1u-induced and significantly attenuated Ad-HDAC3-induced HO-1 proteins (Fig. 3D). Immunofluorescence staining revealed that overexpression of XBP1u or HDAC3 increased the nuclear localization of Nrf2 protein (Fig. 3E). Importantly, overexpression of XBP1u or HDAC3 not only increased HO-1 protein in the infected cells but also in adjacent cells (Fig. 3E), suggesting that some secreted factors are involved. These results suggest that XBP1u or HDAC3 promotes EC survival under oxidative stress through Nrf2-mediated HO-1 expression.
Affiliation: From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.