Abstract
Cardiac fibrosis is a common precursor to ventricular dysfunction and eventual heart failure, and cardiac fibrosis begins with cardiac fibroblast activation. Here we have demonstrated that the TGF-β signaling pathway and Wnt signaling pathway formed a transactivation circuit during cardiac fibroblast activation and that miR-384-5p is a key regulator of the transactivation circuit. The results of in vitro study indicated that TGF-β activated an auto-positive feedback loop by increasing Wnt production in cardiac fibroblasts, and Wnt neutralizing antibodies disrupted the feedback loop. Also, we demonstrated that miR-384-5p simultaneously targeted the key receptors of the TGF-β/Wnt transactivation circuit and significantly attenuated both TGF-β-induced cardiac fibroblast activation and ischemia-reperfusion-induced cardiac fibrosis. In addition, small molecule that prevented pro-fibrogenic stimulus-induced downregulation of endogenous miR-384-5p significantly suppressed cardiac fibroblast activation and cardiac fibrosis. In conclusion, modulating a key endogenous miRNA targeting multiple components of the TGF-β/Wnt transactivation circuit can be an effective means to control cardiac fibrosis and has great therapeutic potential.
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Acknowledgements
This study was supported by grants funded by the Korea Ministry of Science, ICT and Future Planning (NRF-2015M3A9E6029519 and NFR-2015M3A9E6029407).
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Seo, HH., Lee, S., Lee, C.Y. et al. Multipoint targeting of TGF-β/Wnt transactivation circuit with microRNA 384-5p for cardiac fibrosis. Cell Death Differ 26, 1107–1123 (2019). https://doi.org/10.1038/s41418-018-0187-3
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DOI: https://doi.org/10.1038/s41418-018-0187-3
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