Dysregulated post-transcriptional control of COX-2 gene expression in gestational diabetic endothelial cells.
Br J Pharmacol
; 172(18): 4575-4587, 2015 Sep.
Article
en En
| MEDLINE
| ID: mdl-26140661
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-1ß through the induction of long-lasting epigenetic changes involving microRNA-16 (miR-16), a post-transcriptional modulator of COX-2 expression. EXPERIMENTALAPPROACH:
Studies were performed on HUVEC collected from women with gestational diabetes mellitus (GDM) (dHUVEC) and normal women (nHUVEC). KEYRESULTS:
In dHUVEC treated with IL-1ß, 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-1ß, 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-1ß 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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Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Br J Pharmacol
Año:
2015
Tipo del documento:
Article
País de afiliación:
Italia