Multipoint targeting of TGF-β/Wnt transactivation circuit with microRNA 384-5p for cardiac fibrosis

• Published in: Cell death and differentiation Vol. 26; no. 6; pp. 1107 - 1123
• Main Authors: Seo, Hyang-Hee, Lee, Seahyoung, Lee, Chang Youn, Lee, Jiyun, Shin, Sunhye, Song, Byeong-Wook, Kim, Il-Kwon, Choi, Jung-Won, Lim, Soyeon, Kim, Sang Woo, Hwang, Ki-Chul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-06-2019; Nature Publishing Group
• Subjects: 13/95; 14/34; 38/77; 42/89; 631/337; 692/699/75; 82/51; 82/80; 96/98; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell Movement; Cell Proliferation; Congestive heart failure; Embryos; Feedback; Fibroblasts; Fibrosis; Fibrosis - metabolism; Fibrosis - pathology; Ischemia; Life Sciences; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; Myocardium - metabolism; Myocardium - pathology; Rats; Rats, Sprague-Dawley; Reperfusion; Signal transduction; Stem Cells; Transfection; Transforming Growth Factor beta - metabolism; Ventricle; Wnt protein; Wnt Signaling Pathway
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-018-0187-3

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.