The master cytokine TGF-β mediates tissue fibrosis associated with inflammation and tissue injury. TGF-β induces fibroblast activation and differentiation into myofibroblasts that secrete extracellular matrix proteins. Canonical TGF-β signaling mobilizes Smad2 and Smad3 transcription factors that control fibrosis by promoting gene expression. However, the importance of TGF-β–Smad2/3 signaling in fibroblast-mediated cardiac fibrosis has not been directly evaluated in vivo. Here, we examined pressure overload–induced cardiac fibrosis in fibroblast- and myofibroblast-specific inducible Cre-expressing mouse lines with selective deletion of the TGF-β receptors Tgfbr1/2, Smad2, or Smad3. Fibroblast-specific deletion of Tgfbr1/2 or Smad3, but not Smad2, markedly reduced the pressure overload–induced fibrotic response as well as fibrosis mediated by a heart-specific, latency-resistant TGF-β mutant transgene. Interestingly, cardiac fibroblast–specific deletion of Tgfbr1/2, but not Smad2/3, attenuated the cardiac hypertrophic response to pressure overload stimulation. Mechanistically, loss of Smad2/3 from tissue-resident fibroblasts attenuated injury-induced cellular expansion within the heart and the expression of fibrosis-mediating genes. Deletion of Smad2/3 or Tgfbr1/2 from cardiac fibroblasts similarly inhibited the gene program for fibrosis and extracellular matrix remodeling, although deletion of Tgfbr1/2 uniquely altered expression of an array of regulatory genes involved in cardiomyocyte homeostasis and disease compensation. These findings implicate TGF-β–Smad2/3 signaling in activated tissue-resident cardiac fibroblasts as principal mediators of the fibrotic response.

中文翻译：

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成纤维细胞特异性TGF- β – Smad2 / 3信号是心脏纤维化的基础

主细胞因子TGF-β介导与炎症和组织损伤相关的组织纤维化。TGF-β诱导成纤维细胞活化并分化为分泌细胞外基质蛋白的成肌纤维细胞。规范的TGF-β信号转导通过促进基因表达来控制纤维化的Smad2和Smad3转录因子。然而，尚未直接评估体内TGF-β–Smad2 / 3信号在成纤维细胞介导的心脏纤维化中的重要性。在这里，我们检查了成纤维细胞和成肌纤维细胞特异性可诱导Cre表达小鼠系中压力超负荷引起的心脏纤维化，并选择性删除了TGF-β受体Tgfbr1 / 2，Smad2或Smad3。Tgfbr1 / 2或Tgfbr1 / 2的成纤维细胞特异性缺失Smad3而非Smad2显着降低了压力超负荷引起的纤维化反应以及由心脏特异性，耐潜伏性的TGF-β突变体转基因介导的纤维化。有趣的是，心脏成纤维细胞特异的Tgfbr1 / 2的缺失，而不是Smad2 / 3的缺失，减弱了心脏对压力超负荷刺激的肥大反应。从机制上讲，从组织驻留的成纤维细胞中Smad2 / 3的丧失减弱了损伤引起的心脏内细胞膨胀和纤维化介导基因的表达。删除Smad2 / 3或Tgfbr1 / 2尽管Tgfbr1 / 2的缺失独特地改变了涉及心肌细胞稳态和疾病补偿的一系列调控基因的表达，但来自心脏成纤维细胞的类似物也抑制了纤维化和细胞外基质重塑的基因程序。这些发现暗示活化的组织驻留心脏成纤维细胞中的TGF-β–Smad2 / 3信号是纤维化反应的主要介质。