Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow
Autophagy is required for endothelial cell alignment and atheroprotection under physiological blood flow
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DOI：
10.1073/pnas.1702223114
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发表时间：
2017-10-10
影响因子：
11.1
通讯作者：
Rautou, Pierre-Emmanuel
中科院分区：
文献类型：
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作者：
Vion, Anne-Clemence;Kheloufi, Marouane;Rautou, Pierre-Emmanuel
众所周知，动脉粥样硬化病变优先发生在暴露于低SS的区域，并以促炎症、凋亡和衰老的内皮表型为特征。相反，暴露在高SS下的区域可以防止斑块发展，但其机制仍然难以捉摸。自噬是一种保护性机制，允许有缺陷的细胞器和蛋白质循环利用，以维持细胞内环境的稳定。我们的目的是了解内皮自噬在高SS的动脉粥样硬化保护作用中的作用。动脉粥样硬化保护性高SS刺激人和小鼠动脉内皮细胞自噬流量。相反，暴露于低SS的血管内皮细胞由于雷帕霉素(MTOR)的激活、AMPKa的抑制和自噬通量的阻断而表现出低效的自噬。在高胆固醇血症小鼠中，内皮自噬缺陷仅在暴露于高SS的动脉粥样硬化抵抗区域增加斑块负荷；在动脉粥样硬化区域，斑块大小没有变化，在那里内皮自噬流量已经被阻断。在培养细胞和转基因小鼠中，内皮自噬缺陷的特征是内皮与流动方向的对准缺陷，这是内皮细胞健康的标志。这一效应与高SS区内皮细胞凋亡和衰老的增加有关。内皮自噬缺陷也增加了高SS条件下肿瘤坏死因子-α诱导的炎症反应，并降低了抗炎因子KLF-2的表达。总之，这些结果表明，在高SS条件下，充足的内皮自噬通量通过防止内皮细胞凋亡、衰老和炎症来限制动脉粥样硬化斑块的形成。
It has been known for some time that atherosclerotic lesions preferentially develop in areas exposed to lowSS and are characterized by a proinflammatory, apoptotic, and senescent endothelial phenotype. Conversely, areas exposed to high SS are protected from plaque development, but the mechanisms have remained elusive. Autophagy is a protective mechanism that allows recycling of defective organelles and proteins to maintain cellular homeostasis. We aimed to understand the role of endothelial autophagy in the atheroprotective effect of high SS. Atheroprotective high SS stimulated endothelial autophagic flux in human and murine arteries. On the contrary, endothelial cells exposed to atheroprone low SS were characterized by inefficient autophagy as a result of mammalian target of rapamycin (mTOR) activation, AMPKa inhibition, and blockade of the autophagic flux. In hypercholesterolemic mice, deficiency in endothelial autophagy increased plaque burden only in the atheroresistant areas exposed to high SS; plaque size was unchanged in atheroprone areas, in which endothelial autophagy flux is already blocked. In cultured cells and in transgenic mice, deficiency in endothelial autophagy was characterized by defects in endothelial alignment with flow direction, a hallmark of endothelial cell health. This effect was associated with an increase in endothelial apoptosis and senescence in high-SS regions. Deficiency in endothelial autophagy also increased TNF-alpha-induced inflammation under high-SS conditions and decreased expression of the antiinflammatory factor KLF-2. Altogether, these results show that adequate endothelial autophagic flux under high SS limits atherosclerotic plaque formation by preventing endothelial apoptosis, senescence, and inflammation.