Cardiac fibroblasts (CFs) phenotypic conversion to myofibroblasts (MFs) represents a crucial event in cardiac fibrosis that leads to impaired cardiac function. However, regulation of this phenotypic transformation remains unclear. Here, we showed that sirtuin-7 (Sirt7) plays an important role in the regulation of MFs differentiation. Sirt7 expression and phosphorylation were upregulated in CFs upon angiotensin-II (Ang-II) stimulation. Sirt7 depletion by siRNA in CFs resulted in decreased cell proliferation and extracellular matrix (ECM) deposition. Further, examination of Sirt7-depleted CFs demonstrated significantly lower expression of α-smooth muscle actin (α-SMA), the classical marker of MFs differentiation, and decreased formation of focal adhesions. Moreover, overexpression of Sirt7 increased α-SMA expression in Ang-II treated CFs and exacerbated Ang-II-induced MFs differentiation. Moreover, Sirt7 depletion could largely reverse Ang-II induced increase of nuclear translocalization and activity of smad2 and extracellular regulated kinases (ERK) in CFs. Importantly, the increased differentiation of CFs to MFs was also abolished by smad2 siRNA or U0126. Our findings reveal a novel role of Sirt7 and its phosphorylation in the phenotypic conversion of CFs to MFs and might lead to the development of new therapeutic and prognostic tools for cardiac fibrosis.

中文翻译：

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Sirt7的增强表达和磷酸化激活smad2和ERK信号，并在血管紧张素II刺激下促进心脏纤维化的分化。

心脏成纤维细胞（CFs）表型转化为肌成纤维细胞（MFs）代表心脏纤维化中的关键事件，导致心脏功能受损。但是，这种表型转化的调控仍不清楚。在这里，我们表明，sirtuin-7（Sirt7）在调节MFs的分化中起重要作用。在血管紧张素-II（Ang-II）刺激下，CF中的Sirt7表达和磷酸化上调。siRNA在CF中消耗Sirt7导致细胞增殖减少和细胞外基质（ECM）沉积。此外，对Sirt7缺失的CF的检查表明，α-平滑肌肌动蛋白（α-SMA）的表达明显降低，这是MFs分化的经典标志，并减少了粘着斑的形成。而且，Sirt7的过表达增加了Ang-II处理的CF中的α-SMA表达，并加剧了Ang-II诱导的MFs分化。此外，Sirt7耗竭可以在很大程度上逆转Ang-II诱导的CFs中核转位的增加以及smad2和细胞外调节激酶（ERK）的活性。重要的是，smad2 siRNA或U0126也消除了CFs向MFs分化的增强。我们的发现揭示了Sirt7及其在CFs向MFs表型转化中的磷酸化的新作用，并可能导致心脏纤维化的新型治疗和预后工具的发展。smad2 siRNA或U0126也消除了CFs向MFs分化的增强。我们的发现揭示了Sirt7及其在CFs向MFs表型转化中的磷酸化的新作用，并可能导致开发新的用于心脏纤维化的治疗和预后工具。smad2 siRNA或U0126也消除了CFs向MFs分化的增强。我们的发现揭示了Sirt7及其在CFs向MFs表型转化中的磷酸化的新作用，并可能导致开发新的用于心脏纤维化的治疗和预后工具。