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Effect of TFAP4 overexpression on CF function

ABSTRACT: Cardiac fibrosis, is a common pathophysiologic process in nearly all heart diseases, leading to cardiac dysfunction and heart failure subsequently. The transition of cardiac fibroblasts (CFs) to a myofibroblast state underlies the cardiac fibrotic response, and this process is accompanied by changes in the cardiac mechanical environment. Mechanical forces play a central role in the initiation and propagation of fibrosis, resulting in further ECM deposition, crosslinking and reorganization, leading to adverse ventricular remodeling. However, the key factors regulating mechanotransduction during cardiac fibrosis remain unknown. Here we discovered that transcription factor activating enhancer-binding protein 4 (Tfap4) regulates CF migration and proliferation. Further investigation revealed that Tfap4 correlates with heart disease and is significantly upregulated in the fibrotic hearts. We demonstrated that Tfap4 overexpression stimulated CF activation, whereas Tfap4 knockdown resulted in the opposite effect. In addition, we also knocked down Tfap4 in primary human CF (HCFs) with consistent results. Silence of Tfap4 by lentivirus carrying Tfap4 shRNA markedly enhanced functional improvement and scar size reduction in myocardial infarction (MI) mice. Mechanistically, we found that Tfap4 exerts pro-fibrotic function by regulating mechanical stress. Unexpectedly, we found that Tfap4 is a regulator of mechanosensors, Itga11 and Piezo2, thereby involved in mechanotransduction that acts as a bistable switch for the CF phenotypic transition associated with cardiac fibrosis. Taken together, our study revealed that Tfap4 plays an important role in cardiac fibrosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE261406 | GEO | 2025/07/09

REPOSITORIES: GEO

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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.

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Effect of TFAP4 overexpression on CF function

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