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

BACKGROUND AND PURPOSE: Hyperglycemic memory describes the progression of diabetic complications during subsequent periods of improved glycemia.We addressed the hypothesis that transient hyperglycemia causes aberrant cyclooxygenase(COX)-2 expression in human umbilical vein endothelial cells(HUVEC) in response to interleukin(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 AND KEY RESULTS: Studies were performed in HUVEC collected from gestational diabetes mellitus(GDM)(dHUVEC) and normal women(nHUVEC). In dHUVEC treated with IL-1β, we found enhanced expression of COX-2 mRNA and protein and increased generation of prostanoids[the most abundant was the promitogenic prostaglandin(PG)F2α ]. COX-2 mRNA was more stable in dHUVEC and this was associated with miR-16 downregulation and c-Myc induction(a repressor of miR expression). dHUVEC showed higher cellular proliferation in response to IL-1β which was abrogated by COX-2 inhibition and PGF2α receptor antagonism. Comparable changes of 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. Under these experimental conditions, enhanced superoxide anion production was detected. CONCLUSIONS AND IMPLICATIONS: Our results describe a possible mechanism operating in GDM that links enhanced superoxide anion production and epigenetic changes, associated with hyperglycemic 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 glycemic control with agents affecting inflammatory responses and oxidative stress might lead to a more effective prevention of GDM complications.