Background:Conversion of 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 cardiac stromal cells under the control of YAP (yes-associated protein) transcription factor and to validate this finding using a pharmacological agent that interferes with the interactions of the YAP/TAZ (transcriptional coactivator with PDZ-binding motif) complex with their cognate transcription factors TEADs (TEA domain transcription factors), under high-strain and profibrotic stimulation.Methods:We employed high content imaging, 2-dimensional/3-dimensional 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 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:Our experiments suggested that pharmacologically targeting the YAP-dependent pathway overrides the profibrotic activation of cardiac stromal cells by mechanical cues in vitro, and that this occurs even in the presence of profibrotic signaling mediated by TGF-β1 (transforming growth factor beta-1). In vivo administration of Verteporfin in mice with permanent cardiac ischemia reduced significantly fibrosis and morphometric remodeling but did not improve cardiac performance.Conclusions:Our study indicates that preventing molecular translation of mechanical cues in cardiac stromal cells reduces the impact of cardiac maladaptive remodeling with a positive effect on fibrosis.

中文翻译：

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通过干扰 YAP 依赖性反式激活来减少心脏纤维化

背景：心脏基质细胞向肌成纤维细胞的转化通常与缺氧条件、代谢损伤和/或炎症有关，所有这些都是心脏纤维化和心力衰竭的诱发因素。我们假设这种转化也可以通过这些细胞通过激活 Hippo 转录途径对机械信号的反应来介导。我们还测试了维替泊芬对细胞的治疗，维替泊芬是一种已知可阻止 YAP/TAZ 复合物与其同源转录因子 TEAD 结合的药物。结果：我们的实验表明，药理学上靶向 YAP 依赖性通路会覆盖心脏基质细胞的促纤维化激活通过体外机械线索，即使存在由 TGF-β1（转化生长因子 β-1）介导的促纤维化信号，也会发生这种情况。在永久性心肌缺血小鼠体内给予维替泊芬可显着减少纤维化和形态重塑，但不会改善心脏性能。结论：我们的研究表明，阻止心脏基质细胞中机械信号的分子翻译可减少心脏适应不良重塑的影响，并具有积极的作用。对纤维化的影响。