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: In summary, disturbed flow may activate the VEGF receptor in a ligand-independent manner, which in turn induces the formation of a complex among mTORC2, Akt1, XBP1u, and HDAC3. The formation of this complex stabilizes both XBP1u and HDAC3 and activates Akt1 phosphorylation, leading to Nrf2 stabilization. Nrf2 translocates into the nucleus and binds to the ARE in the HMOX-1 gene promoter, promoting HMOX-1 transcription. HO-1 catalyzes heme degradation and produces the antioxidant biliverdin and carbon monoxide. Through these mechanisms, ECs protect themselves from disturbed flow-induced oxidative stress, therefore maintaining the redox homeostasis (Fig. 6).
Affiliation: From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.