Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway
Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway
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DOI：
10.1161/circulationaha.114.014821
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发表时间：
2015-09-22
期刊：
影响因子：
37.8
通讯作者：
Ogawa, Hisao
中科院分区：
文献类型：
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作者：
Araki, Satoshi;Izumiya, Yasuhiro;Ogawa, Hisao
Sirt 7是哺乳动物sirtuin家族的7个成员之一，促进致癌转化。肿瘤生长和转移需要纤维化和血管生成反应。在这里，我们研究了Sirt 7在心血管组织修复process.Methods和结果中的作用，在野生型小鼠，Sirt 7的表达增加，响应急性心血管损伤，包括心肌梗死和后肢缺血，特别是在活跃的伤口愈合部位。与野生型小鼠相比，纯合子Sirt 7缺陷（Sirt 7（-/-））小鼠表现出心肌梗死后心脏破裂的易感性，后肢缺血后血流恢复延迟，皮肤损伤后伤口愈合受损。组织学分析显示，Sirt 7（-/-）小鼠梗死边缘区的纤维化、成纤维细胞分化和炎性细胞浸润减少。在体外，与野生型小鼠来源的或对照siRNA处理的细胞相比，Sirt 7（-/-）小鼠来源的或Sirt 7 siRNA处理的心脏成纤维细胞显示出降低的转化生长因子信号激活和低表达水平的纤维化相关基因。这些变化伴随着转化生长因子受体I蛋白的减少。Sirt 7的缺失激活了心脏成纤维细胞中的自噬。自噬抑制剂可阻断Sirt 7缺失引起的转化生长因子受体I下调，Sirt 7与蛋白激酶C相互作用蛋白的相互作用参与了这一过程。结论Sirt 7通过调节自噬维持转化生长因子受体I的表达，参与组织修复过程。
Background Sirt7, 1 of the 7 members of the mammalian sirtuin family, promotes oncogenic transformation. Tumor growth and metastasis require fibrotic and angiogenic responses. Here, we investigated the role of Sirt7 in cardiovascular tissue repair process.Methods and Results In wild-type mice, Sirt7 expression increased in response to acute cardiovascular injury, including myocardial infarction and hind-limb ischemia, particularly at the active wound healing site. Compared with wild-type mice, homozygous Sirt7-deficient (Sirt7(-/-)) mice showed susceptibility to cardiac rupture after myocardial infarction, delayed blood flow recovery after hind-limb ischemia, and impaired wound healing after skin injury. Histological analysis showed reduced fibrosis, fibroblast differentiation, and inflammatory cell infiltration in the border zone of infarction in Sirt7(-/-) mice. In vitro, Sirt7(-/-) mouse-derived or Sirt7 siRNA-treated cardiac fibroblasts showed reduced transforming growth factor- signal activation and low expression levels of fibrosis-related genes compared with wild-type mice-derived or control siRNA-treated cells. These changes were accompanied by reduction in transforming growth factor receptor I protein. Loss of Sirt7 activated autophagy in cardiac fibroblasts. Transforming growth factor- receptor I downregulation induced by loss of Sirt7 was blocked by autophagy inhibitor, and interaction of Sirt7 with protein interacting with protein kinase-C was involved in this process.Conclusion Sirt7 maintains transforming growth factor receptor I by modulating autophagy and is involved in the tissue repair process.