Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells

Luigia Di Francesco, Melania Dovizio, Annalisa Trenti, Emanuela Marcantoni, Ashleigh Moore, Peadar O'Gaora, Cathal McCarthy, Stefania Tacconelli, Annalisa Bruno, Sara Alberti, Salvatore Gizzo, Giovanni Battista Nardelli, Genny Orso, Orina Belton, Lucia Trevisi, Dan A. Dixon, Paola Patrignani

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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 PGF). 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 PGF 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.

Original languageEnglish
Pages (from-to)4575-4587
Number of pages13
JournalBritish Journal of Pharmacology
Volume172
Issue number18
DOIs
Publication statusPublished - Sep 1 2015

ASJC Scopus subject areas

  • Pharmacology

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    Di Francesco, L., Dovizio, M., Trenti, A., Marcantoni, E., Moore, A., O'Gaora, P., McCarthy, C., Tacconelli, S., Bruno, A., Alberti, S., Gizzo, S., Nardelli, G. B., Orso, G., Belton, O., Trevisi, L., Dixon, D. A., & Patrignani, P. (2015). Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells. British Journal of Pharmacology, 172(18), 4575-4587. https://doi.org/10.1111/bph.13241