Caveolin 1-related autophagy initiated by aldosterone-induced oxidation promotes liver sinusoidal endothelial cells defenestration.
Caveolin 1-related autophagy initiated by aldosterone-induced oxidation promotes liver sinusoidal endothelial cells defenestration.
复制标题
醛固酮诱导氧化引发的 Caveolin 1 相关自噬促进肝窦内皮细胞脱窗
DOI：
10.1016/j.redox.2017.07.011
复制
发表时间：
2017-10
期刊：
影响因子：
11.4
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Luo X;Dan Wang;Luo X;Zhu X;Wang G;Ning Z;Li Y;Ma X;Yang R;Jin S;Huang Y;Meng Y;Li X
具有促氧化和促自噬功能的醛固酮在肝纤维化中起着关键作用。然而，醛固酮促进肝窦内皮细胞(LSECs)去窗的机制仍不清楚。Caveolin 1(Caveolin 1)与自噬和窗口作用密切相关。因此，我们的目标是研究与Cav1相关的自噬在LSECs去窗中的作用。我们发现，在人肝纤维化、BDL或醛固酮增多症模型中，LSECs的醛固酮/MR(盐皮质激素受体)水平升高、氧化、自噬和去窗，而拮抗醛固酮或抑制自噬可减轻BDL诱导的纤维化或高醛固酮症模型中LSECs的去窗作用。在体外，原代LSECs的窗孔逐渐缩小，NO依赖的途径下调，AMPK依赖的自噬增强；雷帕霉素(自噬激活剂)或醛固酮处理会加剧这些影响。此外，醛固酮增加了由Cav1介导的氧化，减少了ATP的产生，随后诱导了AMPK依赖的自噬，导致NO依赖的途径下调和LSECs去窗。这些效应可被MR拮抗剂螺内酯、抗氧化剂或自噬抑制剂逆转。此外，醛固酮还促进了Cav1与p62和泛素的免疫共沉淀，并诱导了LSECs与Lc3、泛素和F-肌动蛋白在核周的免疫荧光染色。此外，醛固酮处理增加了Cav1的膜蛋白水平，而降低了Cav1的胞浆蛋白水平，表明醛固酮诱导了Cav1相关的选择性自噬和F-肌动蛋白重塑，从而促进了去窗。因此，通过激活AMPK-ULK1途径和抑制NO依赖途径，由醛固酮诱导的氧化启动的Cav1相关选择性自噬促进LSECs去窗。
Aldosterone, with pro-oxidation and pro-autophagy capabilities, plays a key role in liver fibrosis. However, the mechanisms underlying aldosterone-promoted liver sinusoidal endothelial cells (LSECs) defenestration remain unknown. Caveolin 1 (Cav1) displays close links with autophagy and fenestration. Hence, we aim to investigate the role of Cav1-related autophagy in LSECs defenestration. We found the increase of aldosterone/MR (mineralocorticoid receptor) level, oxidation, autophagy, and defenestration in LSECs in the human fibrotic liver, BDL or hyperaldosteronism models; while antagonizing aldosterone or inhibiting autophagy relieved LSECs defenestration in BDL-induced fibrosis or hyperaldosteronism models. In vitro, fenestrae of primary LSECs gradually shrank, along with the down-regulation of the NO-dependent pathway and the augment of the AMPK-dependent autophagy; these effects were aggravated by rapamycin (an autophagy activator) or aldosterone treatment. Additionally, aldosterone increased oxidation mediated by Cav1, reduced ATP generation, and subsequently induced the AMPK-dependent autophagy, leading to the down-regulation of the NO-dependent pathway and LSECs defenestration. These effects were reversed by MR antagonist spironolactone, antioxidants or autophagy inhibitors. Besides, aldosterone enhanced the co-immunoprecipitation of Cav1 with p62 and ubiquitin, and induced Cav1 co-immunofluorescence staining with LC3, ubiquitin, and F-actin in the perinuclear area of LSECs. Furthermore, aldosterone treatment increased the membrane protein level of Cav1, whereas decrease the cytoplasmic protein level of Cav1, indicating that aldosterone induced Cav1-related selective autophagy and F-actin remodeling to promote defenestration. Consequently, Cav1-related selective autophagy initiated by aldosterone-induced oxidation promotes LSECs defenestration via activating the AMPK-ULK1 pathway and inhibiting the NO-dependent pathway.
登录
查看更多内容
DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
13.5
作者：
DeLeve, Laurie D.
通讯作者：
DeLeve, Laurie D.
影响因子：
29
作者：
Fernández-Hernando C;Yu J;Suárez Y;Rahner C;Dávalos A;Lasunción MA;Sessa WC
通讯作者：
Sessa WC
影响因子：
13.5
作者：
BRONK, SF;GORES, GJ
通讯作者：
GORES, GJ
影响因子：
7.4
作者：
Chen, Feng;Barman, Scott;Yu, Yanfang;Haigh, Steven;Wang, Yusi;Dou, Huijuan;Bagi, Zsolt;Han, Weihong;Su, Yunchao;Fulton, David J. R.
通讯作者：
Fulton, David J. R.