Abstract
BackgroundDiabetes mellitus is characterized by chronic vascular disorder and presents a main risk factor for cardiovascular mortality. In particular, hyperglycaemia and inflammatory cytokines induce vascular circulating tissue factor (TF) that promotes pro-thrombotic conditions in diabetes. It has recently become evident that alterations of the post-transcriptional regulation of TF via specific microRNA(miR)s, such as miR-126, contribute to the pathogenesis of diabetes and its complications. The endothelial miR-19a is involved in vascular homeostasis and atheroprotection. However, its role in diabetes-related thrombogenicity is unknown. Understanding miR-networks regulating procoagulability in diabetes may help to develop new treatment options preventing vascular complications.Methods and resultsPlasma of 44 patients with known diabetes was assessed for the expression of miR-19a, TF protein, TF activity, and markers for vascular inflammation. High miR-19a expression was associated with reduced TF protein, TF-mediated procoagulability, and vascular inflammation based on expression of vascular adhesion molecule-1 and leukocyte count. We found plasma expression of miR-19a to strongly correlate with miR-126. miR-19a reduced the TF expression on mRNA and protein level in human microvascular endothelial cells (HMEC) as well as TF activity in human monocytes (THP-1), while anti-miR-19a increased the TF expression. Interestingly, miR-19a induced VCAM expression in HMEC. However, miR-19a and miR-126 co-transfection reduced total endothelial VCAM expression and exhibited additive inhibition of a luciferase reporter construct containing the F3 3′UTR.ConclusionsWhile both miRs have differential functions on endothelial VCAM expression, miR-19a and miR-126 cooperate to exhibit anti-thrombotic properties via regulating vascular TF expression. Modulating the post-transcriptional control of TF in diabetes may provide a future anti-thrombotic and anti-inflammatory therapy.
Highlights
Diabetes mellitus is characterized by chronic vascular disorder and presents a main risk factor for cardiovascular mortality
We found a high expression of miR-19a in human microvascular endothelial cells (HMEC) that was reduced upon stimulation with TNF-α (Fig. 3a)
Following treatment with TNF-α for 6 h we observed an increase in VCAM1 upon miR-19a transfection while miR-126 reduced VCAM1 protein. When both miRs were co transfected an overall reduction in VCAM1 protein was observed (Fig. 5b and Additional file 1: Figure S1E). Both miR‐19a and miR‐126 exhibit concomitant inhibition of the F3 3′UTR To analyse whether miR-19a and miR-126, which we found to be co expressed in the patients with diabetes, exhibit a cumulative effect on the 3′untranslated region (UTR) of the tissue factor (TF) (F3) transcript, a luciferase assay was performed in Human embryonic kidney (HEK) cells
Summary
Diabetes mellitus is characterized by chronic vascular disorder and presents a main risk factor for cardiovascular mortality. Hyperglycaemia and inflammatory cytokines induce vascular circulating tissue factor (TF) that promotes pro-thrombotic conditions in diabetes. It has recently become evident that alterations of the post-transcriptional regulation of TF via specific microRNA(miR)s, such as miR-126, contribute to the pathogenesis of diabetes and its complications. Understanding miR-networks regulating procoagulability in diabetes may help to develop new treatment options preventing vascular complications. Diabetes is characterized by a chronic inflammatory state of the vasculature leading to increased cardiovascular complications and death [1]. The small non-coding microRNA(miR)s have been implicated in diabetes and its cardiovascular complications [16, 17]. Mechanistic insights on how those miRs impact diabetic vascular complications are lacking
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