Metformin alters the epigenetic regulation of tissue factor in diabetes

M. Witkowski1, A. Weithauser1, T. Tabaraie1, D. Steffens1, J. Friebel1, A. Doerner1, M. Kasner1, B. Stratmann2, D. Tschoepe2, U. Landmesser1, U. Rauch1 (1Berlin, Germany, 2Bad Oeyenhausen, Germany)

Vascular Wall, Platelets and Acquired Problems
Date: 16.02.2017,
Time: 14:00 - 15:15

Objective: Diabetes mellitus is characterized by chronic vascular inflammation and a main risk factor for cardiovascular mortality. In particular, elevated levels of circulating tissue factor (TF) result in increased diabetes-related thrombogenicity. Metformin remains the first-line therapy for an oral anti-diabetic treatment. Beyond its glucose-lowering effects, metformin was shown to reduce vascular inflammation and levels of circulating coagulation factors, including TF. Recently, metformin has been reported to alter the expression of endothelial microRNA(miR)s, such as miR-19a and miR-126. In the present study we sought to elucidate the role of miR-depending TF expression and procoagulability in patients with or without metformin therapy.

Methods: Plasma samples of 40 patients with known diabetes were assessed for the expression of miR-19a, TF protein, TF activity, and markers for vascular inflammation. Human microvascular endothelial cells (HMEC-1) and monocytes (THP-1) were transfected with a miR-mimic or a control-miR.

Results: In those patients on metformin we observed increased expression of miR-19a as compared to the patients without metformin. We found plasma miR-19a to strongly correlate with miR-126 (r= 0.92, p<0.0001). Metformin treatment was associated with reduced TF protein and TF-mediated procoagulability, while the expression of vascular adhesion molecule-1 was not altered. In HMEC-1 and THP-1 miR-19a transfection led to suppression of TF mRNA, TF protein, and TF activity. miR-19a and miR-126 in concert exhibited additive inhibition of TF expression and activity of a luciferase reporter construct containing the F3 3’UTR.

Conclusion: We conclude that metformin increases the expression of miR-19a and miR-126 in patients with diabetes and thereby epigenetically controls the post-transcriptional TF expression. This mechanism may in part explain the metformin-dependent reduction in cardiovascular mortality.