| Title: |
Vascular miR‐181b controls tissue factor‐dependent thrombogenicity and inflammation in type 2 diabetes |
| Authors: |
Witkowski, Marco; Witkowski, Mario; Saffarzadeh, Mona; Friebel, Julian; Tabaraie, Termeh; Ta Bao, Loc; Chakraborty, Aritra; Dörner, Andrea; Stratmann, Bernd; Tschoepe, Diethelm; Winter, Samantha J.; Krueger, Andreas; Ruf, Wolfram; Landmesser, Ulf; Rauch, Ursula |
| Publication Year: |
2020 |
| Collection: |
FU Berlin: Refubium |
| Subject Terms: |
Diabetes complications; Diabetes mellitus; Endothelial cells; Monocytes; NFκB; PTEN; Thrombosis; Tissue factor; Vascular homeostasis; microRNA; ddc:610 |
| Description: |
BACKGROUND: Diabetes mellitus is characterized by chronic vascular inflammation leading to pathological expression of the thrombogenic full length (fl) tissue factor (TF) and its isoform alternatively-spliced (as) TF. Blood-borne TF promotes factor (F) Xa generation resulting in a pro-thrombotic state and cardiovascular complications. MicroRNA (miR)s impact gene expression on the post-transcriptional level and contribute to vascular homeostasis. Their distinct role in the control of the diabetes-related procoagulant state remains poorly understood. METHODS: In a cohort of patients with poorly controlled type 2 diabetes (n = 46) plasma levels of miR-181b were correlated with TF pathway activity and markers for vascular inflammation. In vitro, human microvascular endothelial cells (HMEC)-1 and human monocytes (THP-1) were transfected with miR-181b or anti-miR-181b and exposed to tumor necrosis factor (TNF) α or lipopolysaccharides (LPS). Expression of TF isoforms, vascular adhesion molecule (VCAM) 1 and nuclear factor (NF) κB nuclear translocation was assessed. Moreover, aortas, spleen, plasma, and bone marrow-derived macrophage (BMDM)s of mice carrying a deletion of the first miR-181b locus were analyzed with respect to TF expression and activity. RESULTS: In patients with type 2 diabetes, plasma miR-181b negatively correlated with the procoagulant state as evidenced by TF protein, TF activity, D-dimer levels as well as markers for vascular inflammation. In HMEC-1, miR-181b abrogated TNFα-induced expression of flTF, asTF, and VCAM1. These results were validated using the anti-miR-181b. Mechanistically, we confirmed a miR-181b-mediated inhibition of importin-α3 (KPNA4) leading to reduced nuclear translocation of the TF transcription factor NFκB. In THP-1, miR-181b reduced both TF isoforms and FXa generation in response to LPS due to targeting phosphatase and tensin homolog (PTEN), a principal inducer for TF in monocytes. Moreover, in miR-181-/- animals, we found that reduced levels of miR-181b were accompanied by ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| DOI: |
10.17169/refubium-26825 |
| DOI: |
10.1186/s12933-020-0993-z |
| Availability: |
https://refubium.fu-berlin.de/handle/fub188/27064; https://doi.org/10.17169/refubium-26825; https://doi.org/10.1186/s12933-020-0993-z |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.CF01A1A2 |
| Database: |
BASE |