1. Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells.
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Di Francesco, Luigia, Dovizio, Melania, Trenti, Annalisa, Marcantoni, Emanuela, Moore, Ashleigh, O'Gaora, Peadar, McCarthy, Cathal, Tacconelli, Stefania, Bruno, Annalisa, Alberti, Sara, Gizzo, Salvatore, Nardelli, Giovanni Battista, Orso, Genny, Belton, Orina, Trevisi, Lucia, Dixon, Dan A, and Patrignani, Paola
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GESTATIONAL diabetes ,CYCLOOXYGENASE 2 ,GENETIC regulation ,ENDOTHELIAL cells ,HYPERGLYCEMIA ,EPIGENETICS - Abstract
Background and Purpose: Hyperglycaemic memory describes the progression of diabetic complications during subsequent periods of improved glycaemia. We addressed the hypothesis that transient hyperglycaemia causes aberrant COX-2 expression in HUVEC in response to IL-1β through the induction of long-lasting epigenetic changes involving microRNA-16 (miR-16), a post-transcriptional modulator of COX-2 expression.Experimental Approach: Studies were performed on HUVEC collected from women with gestational diabetes mellitus (GDM) (dHUVEC) and normal women (nHUVEC).Key Results: In dHUVEC treated with IL-1β, the expression of COX-2 mRNA and protein was enhanced and generation of prostanoids increased (the most abundant was the promitogenic PGF2α ). COX-2 mRNA was more stable in dHUVEC and this was associated with miR-16 down-regulation and c-Myc induction (a suppressor of miR expression). dHUVEC showed increased proliferation in response to IL-1β, which was prevented by a COX-2 inhibitor and PGF2α receptor antagonist. Comparable changes in COX-2 mRNA, miR-16 and c-Myc detected in dHUVEC were produced in nHUVEC exposed to transient high glucose and then stimulated with IL-1β under physiological glucose levels; superoxide anion production was enhanced under these experimental conditions.Conclusions and Implications: Our results describe a possible mechanism operating in GDM that links the enhanced superoxide anion production and epigenetic changes, associated with hyperglycaemic memory, to endothelial dysfunction through dysregulated post-transcriptional control of COX-2 gene expression in response to inflammatory stimuli. The association of conventional therapy for glycaemic control with agents affecting inflammatory responses and oxidative stress might lead to a more effective prevention of the complications associated with GDM. [ABSTRACT FROM AUTHOR]- Published
- 2015
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