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Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.

Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, Yu H, Zampetaki A, Hu Y, Xu Q, Zeng L - J. Biol. Chem. (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.

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A schematic illustration of flow-induced HO-1 expression. Disturbed flow (D-Flow) may activate VEGF receptor (KDR) in a ligand-independent manner, which in turn induces the complex formation among mTOR, Akt1, XBP1u, and HDAC3. The complex formation stabilizes both XBP1u and HDAC3 and activates Akt1 phosphorylation (p), leading to Nrf2 stabilization. Nrf2 translocates into nucleus and binds to the ARE in the HMOX-1 gene promoter and recruit co-activators (ca), promoting the HMOX-1 transcription. HO-1 catalyzes the heme degradation, which produces antioxidant biliverdin and carbon monoxide (CO), antagonizing disturbed flow-induced reactive oxygen species (ROS), leading to the maintenance of the redox homeostasis.
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Figure 6: A schematic illustration of flow-induced HO-1 expression. Disturbed flow (D-Flow) may activate VEGF receptor (KDR) in a ligand-independent manner, which in turn induces the complex formation among mTOR, Akt1, XBP1u, and HDAC3. The complex formation stabilizes both XBP1u and HDAC3 and activates Akt1 phosphorylation (p), leading to Nrf2 stabilization. Nrf2 translocates into nucleus and binds to the ARE in the HMOX-1 gene promoter and recruit co-activators (ca), promoting the HMOX-1 transcription. HO-1 catalyzes the heme degradation, which produces antioxidant biliverdin and carbon monoxide (CO), antagonizing disturbed flow-induced reactive oxygen species (ROS), leading to the maintenance of the redox homeostasis.

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).


Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.

Martin D, Li Y, Yang J, Wang G, Margariti A, Jiang Z, Yu H, Zampetaki A, Hu Y, Xu Q, Zeng L - J. Biol. Chem. (2014)

A schematic illustration of flow-induced HO-1 expression. Disturbed flow (D-Flow) may activate VEGF receptor (KDR) in a ligand-independent manner, which in turn induces the complex formation among mTOR, Akt1, XBP1u, and HDAC3. The complex formation stabilizes both XBP1u and HDAC3 and activates Akt1 phosphorylation (p), leading to Nrf2 stabilization. Nrf2 translocates into nucleus and binds to the ARE in the HMOX-1 gene promoter and recruit co-activators (ca), promoting the HMOX-1 transcription. HO-1 catalyzes the heme degradation, which produces antioxidant biliverdin and carbon monoxide (CO), antagonizing disturbed flow-induced reactive oxygen species (ROS), leading to the maintenance of the redox homeostasis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215241&req=5

Figure 6: A schematic illustration of flow-induced HO-1 expression. Disturbed flow (D-Flow) may activate VEGF receptor (KDR) in a ligand-independent manner, which in turn induces the complex formation among mTOR, Akt1, XBP1u, and HDAC3. The complex formation stabilizes both XBP1u and HDAC3 and activates Akt1 phosphorylation (p), leading to Nrf2 stabilization. Nrf2 translocates into nucleus and binds to the ARE in the HMOX-1 gene promoter and recruit co-activators (ca), promoting the HMOX-1 transcription. HO-1 catalyzes the heme degradation, which produces antioxidant biliverdin and carbon monoxide (CO), antagonizing disturbed flow-induced reactive oxygen species (ROS), leading to the maintenance of the redox homeostasis.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.

Show MeSH
Related in: MedlinePlus