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Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes.

ABSTRACT: 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) ? or lipopolysaccharides (LPS). Expression of TF isoforms, vascular adhesion molecule (VCAM) 1 and nuclear factor (NF) ?B 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 TNF?-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-?3 (KPNA4) leading to reduced nuclear translocation of the TF transcription factor NF?B. 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 increased TF, VCAM1, and KPNA4 expression in aortic tissue as well as increased TF and PTEN expression in spleen. Finally, BMDMs of miR-181-/- mice showed increased TF expression and FXa generation upon stimulation with LPS. CONCLUSIONS:miR-181b epigenetically controls the procoagulant state in diabetes. Reduced miR-181b levels contribute to increased thrombogenicity and may help to identify individuals at particular risk for thrombosis.

SUBMITTER: Witkowski M

PROVIDER: S-EPMC7027062 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes.

Witkowski Marco M Witkowski Mario M Saffarzadeh Mona M Friebel Julian J Tabaraie Termeh T Ta Bao Loc L Chakraborty Aritra A Dörner Andrea A Stratmann Bernd B Tschoepe Diethelm D Winter Samantha J SJ Krueger Andreas A Ruf Wolfram W Landmesser Ulf U Rauch Ursula U

Cardiovascular diabetology 20200217 1

<h4>Background</h4>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 d ...[more]

PMID: 32066445

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Dataset Information

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes.

Publications

Vascular miR-181b controls tissue factor-dependent thrombogenicity and inflammation in type 2 diabetes.

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