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Aims/Introduction  Given the high prevalence of diabetes and burn injuries worldwide, it is essential to dissect the underlying mechanism of delayed burn wound healing in diabetes patients, especially the high glucose‐induced hypoxia‐inducible factor 1 ( HIF ‐1)‐mediated transcription defects.    Materials and Methods  Human umbilical vein endothelial cells were cultured with low or high concentrations of glucose.  HIF ‐1α‐induced vascular endothelial growth factor ( VEGF ) transcription was measured by luciferase assay. Immunofluorescence staining was carried out to visualize cyclic adenosine monophosphate response element binding protein ( CREB ) localization. Immunoprecipitation was carried out to characterize the association between  HIF ‐1α/p300/ CREB . To test whether p300,  CREB  or p300+ CREB  co‐overexpression was sufficient to rescue the  HIF ‐1‐mediated transcription defect after high glucose exposure, p300,  CREB  or p300+ CREB  co‐overexpression were engineered, and  VEGF  expression was quantified. Finally,  in vitro  angiogenesis assay was carried out to test whether the high glucose‐induced angiogenesis defect is rescuable by p300 and  CREB  co‐overexpression.    Results  Chronic high glucose treatment resulted in impaired  HIF ‐1‐induced  VEGF  transcription and  CREB  exclusion from the nucleus. P300 or  CREB  overexpression alone cannot rescue high glucose‐induced  HIF ‐1α transcription defects. In contrast, co‐overexpression of p300 and  CREB  dramatically ameliorated high glucose‐induced impairment of  HIF ‐1‐mediated  VEGF  transcription, as well as  in vitro  angiogenesis. Finally, we showed that co‐overexpression of p300 and  CREB  rectifies the dissociation of  HIF ‐1α‐p300‐ CREB  protein complex in chronic high glucose‐treated cells.    Conclusion  Both p300 and  CREB  are required for the function integrity of  HIF ‐1α transcription machinery and subsequent angiogenesis, suggesting future studies to improve burn wound healing might be directed to optimization of the interaction between p300,  CREB  and  HIF ‐1α.

journal of diabetes investigation

Roles of p300 and cyclic adenosine monophosphate response element binding protein in high glucose‐induced hypoxia‐inducible factor 1α inactivation under hypoxic conditions