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

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-? 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-? 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-?/Wnt transactivation circuit and significantly attenuated both TGF-?-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-?/Wnt transactivation circuit can be an effective means to control cardiac fibrosis and has great therapeutic potential.

SUBMITTER: Seo HH

PROVIDER: S-EPMC6748152 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Seo Hyang-Hee HH Lee Seahyoung S Lee Chang Youn CY Lee Jiyun J Shin Sunhye S Song Byeong-Wook BW Kim Il-Kwon IK Choi Jung-Won JW Lim Soyeon S Kim Sang Woo SW Hwang Ki-Chul KC

Cell death and differentiation 20180911 6

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 produc ...[more]

PMID: 30206318

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Project description:Conversion of cardiospheres derived primitive cardiac stromal cells into myofibroblasts is typically associated with hypoxia conditions, metabolic insults, and/or inflammation, all of which are predisposing factors to cardiac fibrosis and heart failure. We hypothesized that this conversion could be also mediated by response of these cells to mechanical cues through activation of the Hippo transcriptional pathway. The objective of the present study was to assess the role of cellular/nuclear straining forces acting in myofibroblast differentiation of cardiospheres derived primitive cardiac stromal cells under the control of YAP transcription factor and to validate this finding using a pharmacological agent that interferes with the interactions of the YAP/TAZ complex with their cognate transcription factors TEADs, under high-strain and pro-fibrotic stimulation. We employed high content imaging, 2D/3D culture, atomic force microscopy mapping and molecular methods to prove the role of cell/nuclear straining in YAP-dependent fibrotic programming in a mouse model of ischemia-dependent cardiac fibrosis and in human-derived primitive cardiospheres derived primitive cardiac stromal cells . We also tested treatment of cells with Verteporfin, a drug known to prevent the association of the YAP/TAZ complex with their cognate transcription factors TEADs. Results suggested that pharmacologically targeting the YAP-dependent pathway overrides the pro-fibrotic activation of cardiospheres derived primitive cardiac stromal cells by mechanical cues in vitro, and that this occurs even in the presence of pro-fibrotic signaling mediated by TGF-β1. In vivo administration of Verteporfin in mice with permanent cardiac ischemia reduced significantly fibrosis and morphometric remodeling but did not improve cardiac performance. Our study indicates that preventing molecular translation of mechanical cues in cardiospheres derived primitive cardiac stromal cells reduces the impact of cardiac maladaptive remodeling with a positive effect on fibrosis.

Dataset Information

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

Publications

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

Similar Datasets

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