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Chaunte Stampley, Anna Lisa Montemari, Folami Lamoke, Curran Dalal, Dennis Marcus, Manuela Bartoli; Hypoxia-stimulated STAT3-dependent VEGF Expression in Retinal Endothelial Cells Involves Activation of Histone Deacetylase 6 (HDAC6). Invest. Ophthalmol. Vis. Sci. 2011;52(14):4359.
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We have previously shown that persistent activation of the transcription factor (TF) signal transducer and activator of transcription 3 (STAT3) leads to hypoxia-induced VEGF expression in the ischemic retina and in retinal cells exposed to hypoxia. Recent studies have also shown that cytosolic histone deacetylases (HDACs) may control the activity of TFs including STAT3. Here we wanted to investigate the specific role of HDAC6, a cytosolic HDAC, on hypoxia-induced STAT3 activation and STAT3-dependent VEGF expression
Retinal microvascular endothelial cells (REC) were exposed to hypoxic condition (pO2=2%) for different times (10, 30 and 60 minutes and for 6,12 and 24 hours). Western blotting analysis was conducted to determine phosphorylation/activation of STAT3 and VEGF protein levels. Immunoprecipitation was performed to determine HDAC6 and STAT3 interaction. Chromatin immunoprecipitation (ChIP) was conducted to assess STAT3 binding to VEGF promoter. HDAC6 activity was measured by determining deacetylation of alpha tubulin. Selective blockade of HDAC6 was achieved by transfection of RECs with specific siRNAs
Hypoxia- stimulated HDAC6 activity, as shown by decreased acetylation of apha tubulin. This effect was associated with increased STAT3 activation (10 and 30 minutes) and binding to VEGF promoter (10 minutes). Hypoxia also stimulated HDAC6 interaction with STAT3 at the same time points. Transfection of RECs with HDAC6 specific siRNAs did not affect hypoxia-induced STAT3 phosphorylation, but blunted its ability to bind VEGF promoter and stimulate VEGF expression
Our data suggest that STAT3 interaction with HDAC6 is necessary to transcription factor binding to VEGF promoter and induction of gene expression. Targeting of HDAC6 may have therapeutic value for the treatment of ischemic retinopathies
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