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https://doi.org/10.1161/res.123.suppl_1.300
Copy DOIJournal: Circulation Research | Publication Date: Aug 3, 2018 |
Citations: 1 |
Introduction: Fibrosis is a major contributor to cardiac disease. MicroRNA-21 (miR-21) has been implicated as a regulator of fibrosis, with inhibitors of miR-21 currently undergoing clinical trials. We aimed to explore how miR-21 inhibition attenuates fibrosis using a proteomics approach. Methods and Results: As expected, transfection with miR-21 mimics and inhibitors altered the proliferation of murine cardiac fibroblasts. However, proteomic analysis of their conditioned media revealed limited effects on ECM secretion. Similarly, proteomic analysis of hearts from miR-21 null mice showed no major difference in extracellular matrix (ECM) composition. Thus, we searched for additional explanations as to how miR-21 might regulate fibrosis. In the community-based Bruneck study (year 2000 follow-up, n=671), we compared circulating miR-21 with a panel of 229 proteins associated with cardiovascular disease. Several platelet-derived pro-fibrotic factors correlated with plasma miR-21 levels, including the latency-associated peptide of transforming growth factor beta-1 (TGF-β1). This correlation was confirmed by ELISA measurements of active TGF-β1 in plasma (Bruneck 2015 follow-up, n=332). In agreement with this observation in men, systemic inhibition of miR-21 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. AntagomiR-21 treatment, however, had no effect on the platelet count or their aggregation response. In contrast, miR-21 null mice had significantly lower platelet counts compared to littermate controls. Conclusions: This study reports a previously unrecognized effect of miR-21 inhibition on platelets. Both genetic deletion of miR-21 and antagomiR treatment affect platelets. The effect of miR-21 inhibition on platelet TGF-β1 release, in particular, may contribute to the anti-fibrotic effects of miR-21 inhibitors.
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