Multipoint targeting of TGF-β/Wnt transactivation circuit with microRNA 384-5p for cardiac fibrosis
Authors
Hyang-Hee Seo ; Seahyoung Lee ; Chang Youn Lee ; Jiyun Lee ; Sunhye Shin ; Byeong-Wook Song ; Il-Kwon Kim ; Jung-Won Choi ; Soyeon Lim ; Sang Woo Kim ; Ki-Chul Hwang
Citation
CELL DEATH AND DIFFERENTIATION, Vol.26(6) : 1107-1123, 2019-06
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-beta 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-beta 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-beta/Wnt transactivation circuit and significantly attenuated both TGF-beta-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-beta/Wnt transactivation circuit can be an effective means to control cardiac fibrosis and has great therapeutic potential.