Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells.
Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells.
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DOI：
10.1016/j.trsl.2016.05.003
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发表时间：
2016-10
期刊：
影响因子：
--
通讯作者：
Jin ZG
中科院分区：
文献类型：
--
作者：
Xu S;Koroleva M;Yin M;Jin ZG
动脉粥样硬化是一种与机械生物学相关的疾病，主要发生在主动脉弓(AA)和暴露于扰动/湍流血流(DF)的动脉分支，而在血流模式为稳定层流(LF)的胸主动脉(TA)较少。越来越多的证据支持具有高切应力的稳定层流对动脉粥样硬化具有保护作用。然而，LF介导的动脉粥样硬化保护的分子机制仍不完全清楚。河马/YAP(Yes-Associated Protein，是相关蛋白)通路可以感知和影响机械信号，被认为是细胞增殖、分化和组织内稳态的主要调节因子。在这里，我们显示了LF调节内皮细胞(ECs)中YAP的活性。我们观察到YAP在小鼠富含内皮细胞的组织(肺和主动脉)和人内皮细胞中高表达。此外，我们还发现，在载脂蛋白E−/−小鼠和人内皮细胞中，LF通过促进依赖于LATS1/2的YAP(Ser127)的磷酸化，降低了核YAP蛋白水平和YAP靶基因的表达(cTGF和Cyr61)。在功能上，我们发现YAP在内皮细胞表型复制LF反应中的耗竭，减少了细胞周期基因Cyclin A1(CCNA1)和促炎基因CCL2(MCP-1)的表达。综上所述，我们证明了具有动脉粥样硬化保护作用的LF抑制了内皮细胞YAP的激活，这可能有助于LF介导的内皮细胞的静止和抗炎。
Atherosclerosis is a mechanobiology-related disease that preferentially develops in the aortic arch (AA) and arterial branches which are exposed to disturbed/turbulent blood flow (DF), but less in thoracic aorta (TA) where the flow pattern is steady laminar flow (LF). Increasing evidence supports that steady laminar flow with high shear stress is protective against atherosclerosis. However, the molecular mechanisms of LF mediated atheroprotection remain incompletely understood. Hippo/YAP (Yes-associated protein) pathway senses and effects mechanical cues, and has been reported to be a master regulator of cell proliferation, differentiation, and tissue homeostasis. Here we show that LF regulates YAP activity in endothelial cells (ECs). We observed that YAP is highly expressed in mouse EC-enriched tissues (lung and aorta) and in human ECs. Furthermore, we found in ApoE−/−mice and human ECs, LF decreased the levels of nuclear YAP proteins and YAP target gene expression (CTGF and Cyr61) through promoting Hippo kinases LATS1/2-dependent YAP (Ser127) phosphorylation. Functionally, we revealed that YAP depletion in ECs phenocopying LF responses, reduced the expression of cell cycle gene cyclin A1 (CCNA1) and pro-inflammatory gene CCL2 (MCP-1). Taken together, we demonstrate that atheroprotective LF inhibits endothelial YAP activation, which may contributes to LF-mediated ECs quiescence and anti-inflammation.
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DOI：
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发表时间：
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期刊：
The Journal of cell biology
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