Back to Search
Start Over
Inhibition of profibrotic microRNA-21 affects platelets and their releasate
- Publisher :
- American Society for Clinical Investigation
-
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.
- Subjects :
- Platelets
Blood Platelets
Male
Proteomics
RNA, Untranslated
Noncoding RNAs
Cardiology
Transforming Growth Factor beta1
Mice
Animals
Humans
Prospective Studies
Aged
Aged, 80 and over
Clinical Trials as Topic
Myocardium
Cell Biology
Fibroblasts
Middle Aged
Fibrosis
3. Good health
Extracellular Matrix
Mice, Inbred C57BL
MicroRNAs
Female
Wiskott-Aldrich Syndrome Protein
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi...........b85627f088c6120a08f79aec84229ed9