Autophagic degradation of caveolin-1 promotes liver sinusoidal endothelial cells defenestration.
Autophagic degradation of caveolin-1 promotes liver sinusoidal endothelial cells defenestration.
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Caveolin-1自噬降解促进肝窦内皮细胞脱窗
DOI：
10.1038/s41419-018-0567-0
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Luo X;Wang D;Zhu X;Wang G;You Y;Ning Z;Li Y;Jin S;Huang Y;Hu Y;Chen T;Meng Y;Li X
自噬与肌动蛋白骨架和一氧化氮依赖通路相互作用，可能影响内皮细胞的表型和功能。此外，cavo -1 （cavo -1）作为肝窦内皮细胞（LSECs）的结构蛋白，与自噬密切相关。因此，我们的目的是探讨Cav-1自噬降解在LSECs脱巢中的作用。在体内，我们发现人肝纤维化后肝窦内皮细胞自噬增加。此外，在ccl4诱导的LSECs脱巢过程中，引发了自噬、Cav-1降解和肌动蛋白丝（F-actin）重塑；相反，自噬抑制剂3MA减少Cav-1的降解，以维持fenestration和缓解ccl4诱导的纤维化。在体外，在LSECs脱巢过程中，no依赖通路通过PI3K-AKT-MTOR通路的减少和Cav-1自噬降解的启动而下调；然而，饥饿加剧了这些影响。然而，VEGF通过激活PI3K-AKT-MTOR通路抑制Cav-1的自噬降解和F-actin重塑来维持LSECs的开窗。此外，抑制自噬，如3MA、巴菲霉素或ATG5-siRNA，可以减轻Cav-1和f -肌动蛋白重塑的消耗，以维持LSECs的开放并改善no依赖途径；反过来，eNOS-siRNA和L-NAME阻断no依赖途径，可提高Cav-1的自噬降解，从而加剧脱巢。最后，过表达的Cav-1挽救了雷帕霉素诱导的Cav-1自噬降解，以维持LSECs的开窗；而由于ampk依赖性自噬的激活，Cav-1的下调促进了脱巢。因此，Cav-1的自噬降解通过抑制no依赖途径和f -肌动蛋白重塑促进LSECs脱巢。
Autophagy, interacting with actin cytoskeleton and the NO-dependent pathway, may affect the phenotype and function of endothelial cells. Moreover, caveolin-1 (Cav-1), as a structure protein in liver sinusoidal endothelial cells (LSECs), is closely related to autophagy. Hence, we aim to explore the role of autophagic degradation of Cav-1 in LSECs defenestration. In vivo, we found the increase of autophagy in liver sinusoidal endothelium in human fibrotic liver. Furthermore, autophagy, degradation of Cav-1, and actin filament (F-actin) remodeling were triggered during the process of CCl4-induced LSECs defenestration; in contrast, autophagy inhibitor 3MA diminished the degradation of Cav-1 to maintain fenestrae and relieve CCl4-induced fibrosis. In vitro, during LSECs defenestration, the NO-dependent pathway was down-regulated through the reduction of the PI3K–AKT–MTOR pathway and initiation of autophagic degradation of Cav-1; while, these effects were aggravated by starvation. However, VEGF inhibited autophagic degradation of Cav-1 and F-actin remodeling to maintain LSECs fenestrae via activating the PI3K–AKT–MTOR pathway. Additionally, inhibiting autophagy, such as 3MA, bafilomycin, or ATG5-siRNA, could attenuate the depletion of Cav-1 and F-actin remodeling to maintain LSECs fenestrae and improve the NO-dependent pathway; in turn, eNOS-siRNA and L-NAME, for blocking the NO-dependent pathway, could elevate autophagic degradation of Cav-1 to aggravate defenestration. Finally, overexpressed Cav-1 rescued rapamycin-induced autophagic degradation of Cav-1 to maintain LSECs fenestrae; whereas knockdown of Cav-1 facilitated defenestration due to the activation of the AMPK-dependent autophagy. Consequently, autophagic degradation of Cav-1 promotes LSECs defenestration via inhibiting the NO-dependent pathway and F-actin remodeling.
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影响因子：
13.5
作者：
DeLeve, Laurie D.
通讯作者：
DeLeve, Laurie D.
DOI：
10.1152/ajpgi.00069.2008
发表时间：
2008-07-01
影响因子：
4.5
作者：
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通讯作者：
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影响因子：
25.7
作者：
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影响因子：
13.3
作者：
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通讯作者：
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影响因子：
7.8
作者：
Esser, S;Wolburg, K;Wolburg, H;Breier, G;Kurzchalia, T;Risau, W
通讯作者：
Risau, W