Endothelial Autophagy Does Not Influence Venous Thrombosis in Mice
Endothelial Autophagy Does Not Influence Venous Thrombosis in Mice
复制标题
内皮自噬不影响小鼠静脉血栓形成
DOI：
10.1055/s-0038-1641753
复制
发表时间：
2018
影响因子：
6.7
通讯作者：
Boulanger CM
中科院分区：
文献类型：
--
作者：
Rautou PE;Busse J;Kheloufi M;Vion AC;Boulaftali Y;Stark K;Boulanger CM
巨噬，在这里被称为“自噬”，对于细胞稳态和应激适应至关重要，并且构成了一个促进溶酶体降解隔离在自噬体内的细胞内物质的过程。在衰老的生物体中，自噬变得不足，威胁到它们的功能和生存。此外，自噬在多种慢性疾病（包括但不限于感染性、肿瘤性和神经退行性疾病）中不能维持细胞功能。最近的几项研究揭示了自噬在止血和血栓形成中的作用（图1A）。在血小板中，自噬机制在静息条件下具有组成性活性。2 .血小板特异性缺失Atg7（自噬级联的关键蛋白）的小鼠血小板数量和大小分布正常，但在尾出血实验中表现出较强的出血能力，在fecl3诱导的颈动脉损伤模型（动脉血栓形成模型）中表现出较长的闭塞时间。2自噬也有助于内皮细胞的止血。事实上，自噬调节细胞内细胞器（即韦贝尔-帕拉德小体）内皮细胞分泌血管性血友病因子。内皮特异性缺失Atg7的小鼠表现出肾上腺素刺激的血管性血友病因子释放受损，高分子量血管性血友病因子多体水平降低，出血时间相应延长。内皮细胞自噬在动脉血栓形成中的作用也被研究。与野生型动物相比，内皮特异性缺失Atg7的小鼠在FeCl3损伤后颈动脉和肠系膜动脉闭塞的时间延长。此外，这些内皮细胞自噬缺陷小鼠的特点是激光损伤的硬化小动脉血栓较小。综上所述，这些结果表明血小板或内皮细胞中自噬蛋白Atg7的缺陷会导致出血倾向，包括出血时间延长和动脉损伤后闭塞时间增加。自噬在静脉血栓形成中的作用尚不清楚。我们最近报道，在培养细胞和转基因小鼠中，内皮细胞自噬缺陷导致暴露于高剪切应力区域的内皮细胞出现促炎、促衰老和促凋亡表型。内皮细胞凋亡可导致内皮下层暴露于血流，从而促进血小板粘附和血栓形成。这促使我们对缺乏内皮细胞自噬的小鼠体内静脉血栓形成进行分析。
Macroautophagy, herein referred to as ‘autophagy’, is essential for cellular homeostasis and stress adaptation and constitutes a process that facilitates the lysosomal degradation of intracellular material sequestered within autophagosomes. Autophagy becomes insufficient in aging organisms, threatening their functionality and survival. 1 Moreover, autophagy fails to maintain cellular functions in multiple chronic diseases including (but not limited to) infectious, neoplastic and neurodegenerative diseases. 1 Several recent studies have shed light on the role of autophagy in haemostasis and thrombosis (► Fig. 1A). In platelets, autophagy machinery is constitutively active under resting conditions. 2 Mice with platelet-specific deletion of Atg7, a key protein of the autophagy cascade, have normal platelet numbers and size distributions, but exhibit a robust bleeding diathesis in the tail-bleeding assay and a prolonged occlusion time in the FeCl3-induced carotid injury model, a model of arterial thrombosis. 2 Autophagy also contributes to haemostasis in endothelial cells. Indeed, autophagy regulates endothelial secretion of von Willebrand factor from intracellular organelles, known as Weibel–Palade bodies. Mice with endothelial-specific deletion of Atg7 exhibit impaired epinephrine-stimulated von Willebrand factor release, reduced levels of high-molecular weight von Willebrand factor multimers and a corresponding prolongation of the bleeding time. 3 The role of endothelial autophagy in arterial thrombosis has also been investigated. When compared with wild-type animals, mice with endothelial-specific deletion of Atg7 exhibit prolonged time to carotid and mesenteric artery occlusion following FeCl3 injury. Furthermore, these mice deficient in endothelial autophagy are characterized by smaller thrombi in laserinjured cremasteric arterioles. 4 Altogether, these results show that a defect in the autophagy protein Atg7 in platelets or in endothelial cells induces a bleeding tendency including prolonged bleeding time and increased time to occlusion following arterial injury. The role of autophagy in venous thrombosis is unknown.We recently reported that deficiency in endothelial autophagy in cultured cells and in transgenic mice led to a pro-inflammatory, pro-senescent and pro-apoptotic phenotype of endothelial cells exposed to high shear stress areas. 5 Endothelial apoptosis can result in exposure of the subendothelium to blood flow, which would then promote platelet adhesion and thrombosis. 6 This prompted us to analyse in vivo venous thrombus formation in mice deficient in endothelial autophagy.
登录
查看更多内容
DOI：
10.1084/jem.20112322
发表时间：
2012-04-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
von Brühl ML;Stark K;Steinhart A;Chandraratne S;Konrad I;Lorenz M;Khandoga A;Tirniceriu A;Coletti R;Köllnberger M;Byrne RA;Laitinen I;Walch A;Brill A;Pfeiler S;Manukyan D;Braun S;Lange P;Riegger J;Ware J;Eckart A;Haidari S;Rudelius M;Schulz C;Echtler K;Brinkmann V;Schwaiger M;Preissner KT;Wagner DD;Mackman N;Engelmann B;Massberg S
通讯作者：
Massberg S
DOI：
10.1073/pnas.1702223114
发表时间：
2017-10-10
影响因子：
11.1
作者：
Vion, Anne-Clemence;Kheloufi, Marouane;Rautou, Pierre-Emmanuel
通讯作者：
Rautou, Pierre-Emmanuel
DOI：
10.1016/j.jtcvs.2017.02.058
发表时间：
2017-09
期刊：
The Journal of Thoracic and Cardiovascular Surgery
影响因子：
--
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
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
影响因子：
15.9
作者：
Mackman, Nigel
通讯作者：
Mackman, Nigel
影响因子：
20.3
作者：
Brill, Alexander;Fuchs, Tobias A.;Wagner, Denisa D.
通讯作者：
Wagner, Denisa D.