Histone deacetylase 3 (HDAC3), a member of the class I histone deacetylases, is known to have a crucial role in endothelial cell differentiation1 2 and maintenance of endothelial integrity in response to disturbed flow.3 In this study, we investigated the function of HDAC3 in endothelial protection from inflammation, and the underlying mechanism. The inflammatory mediator lipopolysaccharides (LPS) induced HDAC3 and galectin-9 production in a similar pattern in human umbilical vein endothelial cells. Overexpression of HDAC3 by adenoviral gene transfer increased galectin-9 expression. Pharmacological inhibition of HDAC activity with a pan-HDAC inhibitor (TSA) or HDAC3 specific inhibitor (apicidin) reduced the baseline and LPS-induced galectin-9 expression. In addition, knockdown of HDAC3 through shRNA lentiviral transfection abolished the baseline and LPS-induced galectin-9 expression. Similar results were observed on interferon γ (IFNγ)-induced galectin-9 expression. To explore the underlying mechanism, the interaction of HDAC3 with galectin-9 upstream signal pathway phosphoinositol-3-kinase (PI3K)/signal transmission and transducer 3 (Stat3)/interferon response factor (IRF3) was assessed. Co-immunoprecipitation assay showed that HDAC3 formed a complex with PI3K/Stat3/IRF3, which was enhanced by LPS and IFNγ treatment. Using truncated forms of HDAC3, it was shown that the C-terminal of HDAC3 was responsible for the formation of the complex. Furthermore, venous administration of LPS or IFNγ to mice increased HDAC3 expression and binding to the above-mentioned proteins, leading to galectin-9 expression in the aorta. These results suggest that HDAC3 may protect endothelial cell from inflammation through galectin-9 expression, which may have an impact on preventing vascular inflammation related to the development of atherosclerosis.
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