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

Barwari, Temo, Eminaga, Seda, Mayr, Ursula, Lu, Ruifang, Armstrong, Paul C., Chan, Melissa V., Sahraei, Mahnaz, Fernández-Fuertes, Marta, Moreau, Thomas, Barallobre-Barreiro, Javier, Lynch, Marc, Yin, Xiaoke, Schulte, Christian, Baig, Ferheen, Pechlaner, Raimund, Langley, Sarah R. ORCID: https://orcid.org/0000-0003-4419-476X, Zampetaki, Anna, Santer, Peter, Weger, Martin, Plasenzotti, Roberto, Schosserer, Markus, Grillari, Johannes, Kiechl, Stefan, Willeit, Johann, Shah, Ajay M, Ghevaert, Cedric, Warner, Timothy D., Fernández-Hernando, Carlos, Suárez, Yajaira and Mayr, Manuel 2018. Inhibition of profibrotic microRNA-21 affects platelets and their releasate. JCI Insight 3 (21) , e123335. 10.1172/jci.insight.123335

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Biosciences
Publisher:	American Society for Clinical Investigation
ISSN:	2379-3708
Date of First Compliant Deposit:	11 September 2023
Date of Acceptance:	26 September 2018
Last Modified:	11 Sep 2023 20:06
URI:	https://orca.cardiff.ac.uk/id/eprint/162161

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