Endothelial‐specific deletion of autophagy‐related 7 (ATG7) attenuates arterial thrombosis in mice
Endothelial‐specific deletion of autophagy‐related 7 (ATG7) attenuates arterial thrombosis in mice
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DOI：
10.1016/j.jtcvs.2017.02.058
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发表时间：
2017-09
期刊：
影响因子：
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通讯作者：
Jonathan W. Yau;Krishna K. Singh;Yan Hou;X. Lei;Azza Ramadan;A. Quan;H. Teoh;W. Kuebler;M. Al-Omran;B. Yanagawa;H. Ni;S. Verma
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文献类型：
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作者：
Jonathan W. Yau;Krishna K. Singh;Yan Hou;X. Lei;Azza Ramadan;A. Quan;H. Teoh;W. Kuebler;M. Al-Omran;B. Yanagawa;H. Ni;S. Verma
血栓形成一直是发病率和死亡率的主要原因。鉴于内皮细胞（ECs）在调节血栓形成中起着核心作用，了解调节血栓形成易感性或抗性的内皮细胞分子线索具有重要的翻译意义。因此，我们评估了内皮细胞自噬在血栓形成中的作用。方法从ECs中有条件地删除必要自噬相关基因7（ATG7）的小鼠（EC-ATG7 - / -小鼠）。采用三种体内血栓形成模型，并以培养的人脐静脉内皮细胞（HUVECs）进行机制研究。结果在HUVECs中沉默atg7，观察到肿瘤坏死因子(TNF)-α -诱导的组织因子（TF）转录水平、蛋白表达和活性降低60%。接受血小板形成前刺激fecl3的EC-ATG7 - / -小鼠颈动脉中TF mRNA水平低于同样处理的野生型（WT）同伴组。与WT小鼠相比，EC-ATG7−/−小鼠在fecl3损伤后颈动脉（2倍）和肠系膜（1.3倍）动脉闭塞时间延长。与WT小鼠相比，EC-ATG7 - / -小鼠在激光损伤的硬化小动脉中产生的血栓更小，出现血栓的时间延长了2.3倍。综上所述，这些结果提供了明确的证据，证明内皮ATG7的丧失可以减轻血栓形成并降低TF的表达。我们的研究结果表明，内皮细胞ATG7和自噬是调节血栓易感性的关键靶点，但此前未被认识到。
BackgroundThrombosis persists as a leading cause of morbidity and mortality. Given that endothelial cells (ECs) play a central role in regulating thrombosis, understanding the molecular endothelial cues that regulate susceptibility or resistance to thrombosis have important translational implications. Accordingly, we evaluated the role of endothelial autophagy in the development of thrombosis.MethodsWe generated mice in which the essentialautophagy-related 7(ATG7) gene was conditionally deleted from ECs (EC-ATG7−/−mice). Three in vivo models of thrombosis were used, and mechanistic studies were conducted with cultured human umbilical vein endothelial cells (HUVECs).ResultsWe silencedATG7in HUVECs and observed >60% decreases in tumor necrosis factor (TNF)-α–induced tissue factor (TF) transcript levels, protein expression, and activity. TF mRNA levels in the carotid arteries of EC-ATG7−/−mice subjected to the prothrombotic stimulus FeCl3were lower than those in the similarly treated wild-type (WT) littermate group. Compared with WT mice, EC-ATG7−/−mice exhibited prolonged time to carotid (2-fold greater) and mesenteric (1.3-fold greater) artery occlusion following FeCl3injury. The thrombi generated in laser-injured cremasteric arterioles were smaller in EC-ATG7−/−mice compared with WT mice, and took 2.3-fold longer to appear.ConclusionsTaken together, these results provide definitive evidence that loss of endothelial ATG7 attenuates thrombosis and reduces the expression of TF. Our findings demonstrate that endothelial ATG7, and thus autophagy, is a critical and previously unrecognized target for modulating the susceptibility to thrombosis.