TY - JOUR
T1 - Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells
AU - Di Francesco, Luigia
AU - Dovizio, Melania
AU - Trenti, Annalisa
AU - Marcantoni, Emanuela
AU - Moore, Ashleigh
AU - O'Gaora, Peadar
AU - McCarthy, Cathal
AU - Tacconelli, Stefania
AU - Bruno, Annalisa
AU - Alberti, Sara
AU - Gizzo, Salvatore
AU - Nardelli, Giovanni Battista
AU - Orso, Genny
AU - Belton, Orina
AU - Trevisi, Lucia
AU - Dixon, Dan A.
AU - Patrignani, Paola
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
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U2 - 10.1111/bph.13241
DO - 10.1111/bph.13241
M3 - Article
AN - SCOPUS:84940459840
VL - 172
SP - 4575
EP - 4587
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 18
ER -