Histone deacetylases (HDACs) play a crucial role in transcriptional regulation through modulation of chromatin structure. The class I HDAC, HDAC3, is involved in maintaining endothelial cell integrity.1 Sustained activation of the x-box binding protein 1 (XBP1), an endoplasmic reticulum stress response transcription factor, results in the development of atherosclerosis in apoE−/− mice.2 HDAC3 and XBP1 are similarly expressed in the bifurcation regions of the aorta. In this study, we investigated whether cross-talk existed between HDAC3 and XBP1, and its role in the maintenance of endothelial cell integrity. Our study demonstrated that disturbed flow upregulated HDAC3 and unspliced XBP1 (XBP1u) protein production through the KDR/PI3K/Akt pathway. Knockdown of XBP1 by shRNA lentiviral transfection ablated disturbed flow-induced HDAC3 upregulation. Similarly to HDAC3, overexpression of XBP1u by adenoviral gene transfer increased Akt phosphorylation at Serine473 and haem oxygenase 1 gene transcription, which showed a protective role in hydrogen peroxide-induced apoptosis of endothelial cells. Co-immunoprecipitation assays demonstrated that HDAC3 physically associates with XBP1u and this could be enhanced by disturbed flow and VEGF treatment. The use of truncated HDAC3 constructs demonstrated that XBP1 binds to the central section of HDAC3. Further experiments indicated that overexpression of XBP1u increased the binding of HDAC3 to IRE1α, Akt and PI3K, especially after VEGF treatment. In contrast, sustained activation of spliced XBP1 decreased HDAC3 protein production through transcriptional suppression, leading to endothelial apoptosis. These results suggest that XBP1u protects endothelial cells from oxidative stress by interacting with HDAC3. Targeting this interaction may provide novel therapeutic strategies for vascular disease via maintaining endothelial integrity.
- Oxidative stress
- disturbed flow
- Akt phosphorylation
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