[HTML][HTML] Hyperglycaemia-induced reciprocal changes in miR-30c and PAI-1 expression in platelets

M Luo, R Li, M Ren, N Chen, X Deng, X Tan, Y Li… - Scientific reports, 2016 - nature.com
M Luo, R Li, M Ren, N Chen, X Deng, X Tan, Y Li, M Zeng, Y Yang, Q Wan, J Wu
Scientific reports, 2016nature.com
Abstract Type 2 diabetic mellitus (DM2) is associated with accelerated thrombotic
complications and is characterized by high levels of plasminogen activator inhibitor-1 (PAI-
1). Recent studies show that human platelets have high levels of miR-30c and synthesize
considerable active PAI-1. The underlying mechanism of how PAI-1 expression is
upregulated in DM2 is poorly understood. We now report that hyperglycaemia-induced
repression of miR-30c increases PAI-1 expression and thrombus formation in DM2 …
Abstract
Type 2 diabetic mellitus (DM2) is associated with accelerated thrombotic complications and is characterized by high levels of plasminogen activator inhibitor-1 (PAI-1). Recent studies show that human platelets have high levels of miR-30c and synthesize considerable active PAI-1. The underlying mechanism of how PAI-1 expression is upregulated in DM2 is poorly understood. We now report that hyperglycaemia-induced repression of miR-30c increases PAI-1 expression and thrombus formation in DM2. Bioinformatic analysis and identification of miRNA targets were assessed using luciferase assays, quantitative real-time PCR and western blots invitro and in vivo. The changes in miR-30c and PAI-1 levels were identified in platelets from healthy and diabetic individuals. We found that miR-30c directly targeted the 3′ UTR of PAI-1 and negatively regulated its expression. miR-30c was negatively correlated with glucose and HbA1c levels in DM2. In HFD-fed diabetic mice, increasing miR-30c expression by lenti-miR-30c significantly decreased the PAI-1 expression and prolonged the time to occlusion in an arterial thrombosis model. Platelet depletion/reinfusion experiments generating mice with selective ablation of PAI-1 demonstrate a major contribution by platelet-derived PAI-1 in the treatment of lenti-miR-30c to thrombus formation. These results provide important implications regarding the regulation of fibrinolysis by platelet miRNA under diabetic mellitus.
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