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JCI Insight. 2018 Nov 2;3(21). pii: 123335. doi: 10.1172/jci.insight.123335.

Inhibition of profibrotic microRNA-21 affects platelets and their releasate.

Author information

1
King's British Heart Foundation Centre, King's College London, London, United Kingdom.
2
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
3
Department of Comparative Medicine and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, USA.
4
Department of Haematology, University of Cambridge, National Health Blood Service Centre, Cambridge, United Kingdom.
5
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
6
Duke-NUS Medical School, Singapore.
7
National Heart Centre Singapore, Singapore.
8
Department of Laboratory Medicine and.
9
Department of Internal Medicine, Bruneck Hospital, Bruneck, Italy.
10
Medical University of Vienna, Institute of Biomedical Research, Vienna, Austria.
11
Christian Doppler Laboratory on Biotechnology of Skin Aging, Department of Biotechnology, BOKU - University of Natural Resources and Life Sciences, Vienna, Austria.

Abstract

Fibrosis is a major contributor to organ disease for which no specific therapy is available. MicroRNA-21 (miR-21) has been implicated in the fibrogenetic response, and inhibitors of miR-21 are currently undergoing clinical trials. Here, we explore how miR-21 inhibition may attenuate fibrosis using a proteomics approach. Transfection of miR-21 mimic or inhibitor in murine cardiac fibroblasts revealed limited effects on extracellular matrix (ECM) protein secretion. Similarly, miR-21-null mouse hearts showed an unaltered ECM composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In plasma samples from the community-based Bruneck Study, we found a marked correlation of miR-21 levels with several platelet-derived profibrotic factors, including TGF-β1. Pharmacological miR-21 inhibition with an antagomiR reduced the platelet release of TGF-β1 in mice. Mechanistically, Wiskott-Aldrich syndrome protein, a negative regulator of platelet TGF-β1 secretion, was identified as a direct target of miR-21. miR-21-null mice had lower platelet and leukocyte counts compared with littermate controls but higher megakaryocyte numbers in the bone marrow. Thus, to our knowledge this study reports a previously unrecognized effect of miR-21 inhibition on platelets. The effect of antagomiR-21 treatment on platelet TGF-β1 release, in particular, may contribute to the antifibrotic effects of miR-21 inhibitors.

KEYWORDS:

Cardiology; Cell Biology; Fibrosis; Noncoding RNAs; Platelets

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