Hsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis.
Hsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis.
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DOI：
10.1016/j.redox.2022.102290
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发表时间：
2022-06
期刊：
影响因子：
11.4
通讯作者：
Ji Y
中科院分区：
文献类型：
--
作者：
Zhao S;Tang X;Miao Z;Chen Y;Cao J;Song T;You D;Zhong Y;Lin Z;Wang D;Shi Z;Tang X;Wang D;Chen S;Wang L;Gu A;Chen F;Xie L;Huang Z;Wang H;Ji Y
内皮功能障碍是动脉粥样硬化的起始过程。热休克蛋白90（Heat shock protein 90，Hsp 90）作为一种分子伴侣，在多种心血管疾病中发挥重要作用。Hsp 90的功能受S-亚硝基化（SNO）的调节。然而，SNO-Hsp 90在动脉粥样硬化过程中内皮功能障碍中的确切作用仍不清楚。本文通过生物素转换试验结合液相色谱-串联质谱（LC-MS/MS）鉴定了内皮细胞中高度S-亚硝基化的Hsp 90。在动脉粥样硬化的人和啮齿动物的动脉粥样硬化以及氧化低密度脂蛋白（oxLDL）处理的EC中观察到SNO-Hsp 90的升高。抑制诱导型一氧化氮合酶（iNOS）或转染Hsp 90半胱氨酸521（Cys 521）突变质粒可降低oxLDL培养的内皮细胞中SNO-Hsp 90的水平。免疫共沉淀和邻位连接实验表明，SNO-Hsp 90在Cys 521处抑制了Hsp 90与Hsp 90 ATP酶活性激活剂1（AHA 1）的相互作用，但促进了Hsp 90与细胞分裂周期37（CDC 37）的结合。热休克蛋白90 Cys 521突变增加内皮型一氧化氮合酶（eNOS）活性，抑制核因子-κ B（NF-κB）信号通路，从而增加一氧化氮（NO）生物利用度，减轻oxLDL处理的内皮细胞粘附、炎症和氧化应激。此外，给予Cys 521突变的Hsp 90的内皮特异性腺相关病毒显著减轻了高脂饮食喂养的ApoE-/-小鼠中的血管氧化应激、巨噬细胞浸润和动脉粥样硬化病变面积。总之，在Cys 521处的SNO-Hsp 90作为构象开关，破坏Hsp 90/AHA 1相互作用，但促进募集CDC 37以加剧动脉粥样硬化。Hsp 90在Cys 521处的S-亚硝基化作为构象开关调节Hsp 90/AHA 1和Hsp 90/CDC 37相互作用。SNO-Hsp 90诱导内皮粘附、炎症和氧化应激。SNO-Hsp 90介导内皮功能障碍加重动脉粥样硬化。
Endothelial dysfunction is the initial process of atherosclerosis. Heat shock protein 90 (Hsp90), as a molecular chaperone, plays a crucial role in various cardiovascular diseases. Hsp90 function is regulated by S-nitrosylation (SNO). However, the precise role of SNO-Hsp90 in endothelial dysfunction during atherosclerosis remains unclear. We here identified Hsp90 as a highly S-nitrosylated target in endothelial cells (ECs) by biotin switch assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The elevation of SNO-Hsp90 was observed in atherosclerotic human and rodent aortas as well as in oxidized LDL (oxLDL)-treated ECs. Inhibition of inducible nitric oxide synthase (iNOS) or transfection with Hsp90 cysteine 521 (Cys521) mutation plasmid decreased the level of SNO-Hsp90 in oxLDL-cultured ECs. Coimmunoprecipitation and proximity ligation assay demonstrated that SNO-Hsp90 at Cys521 suppressed the interaction between Hsp90 and activator of Hsp90 ATPase activity 1 (AHA1), but promoted the association of Hsp90 and cell division cycle 37 (CDC37). Hsp90 Cys521 mutation increased endothelial nitric oxide synthase (eNOS) activity and inhibited nuclear factor kappa-B (NF-κB) signaling, thereby increasing nitric oxide (NO) bioavailability and alleviating endothelial adhesion, inflammation and oxidative stress in oxLDL-treated ECs. Also, administration of endothelial-specific adeno-associated viruses of Cys521-mutated Hsp90 significantly mitigated vascular oxidative stress, macrophage infiltration and atherosclerosis lesion areas in high fat diet-fed ApoE-/- mice. In conclusion, SNO-Hsp90 at Cys521, that serves as a conformational switch, disrupts Hsp90/AHA1 interaction but promotes recruitment of CDC37 to exacerbate atherosclerosis. Hsp90 S-nitrosylation at Cys521 acts as a conformational switch to modulate Hsp90/AHA1 and Hsp90/CDC37 interaction. SNO-Hsp90 induces endothelial adhesion, inflammation and oxidative stress. SNO-Hsp90 mediates endothelial dysfunction to exacerbate atherosclerosis.
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影响因子：
16
作者：
Mollapour, Mehdi;Tsutsumi, Shinji;Donnelly, Alison C.;Beebe, Kristin;Tokita, Mari J.;Lee, Min-Jung;Lee, Sunmin;Morra, Giulia;Bourboulia, Dimitra;Scroggins, Bradley T.;Colombo, Giorgio;Blagg, Brian S.;Panaretou, Barry;Stetler-Stevenson, William G.;Trepel, Jane B.;Piper, Peter W.;Prodromou, Chrisostomos;Pearl, Laurence H.;Neckers, Len
通讯作者：
Neckers, Len
DOI：
10.1161/atvbaha.112.256008
发表时间：
2012-10-01
影响因子：
8.7
作者：
Desjardins, Fanny;Delisle, Chantal;Gratton, Jean-Philippe
通讯作者：
Gratton, Jean-Philippe
DOI：
10.1080/10409238.2017.1304353
发表时间：
2017-06
影响因子：
6.5
作者：
Barnett SD;Buxton ILO
通讯作者：
Buxton ILO
影响因子：
16
作者：
Mollapour, Mehdi;Bourboulia, Dimitra;Beebe, Kristin;Woodford, Mark R.;Polier, Sigrun;Hoang, Anthony;Chelluri, Raju;Li, Yu;Guo, Allan;Lee, Min-Jung;Fotooh-Abadi, Elham;Khan, Sahar;Prince, Thomas;Miyajima, Naoto;Yoshida, Soichiro;Tsutsumi, Shinji;Xu, Wanping;Panaretou, Barry;Stetler-Stevenson, William G.;Bratslavsky, Gennady;Trepel, Jane B.;Prodromou, Chrisostomos;Neckers, Len
通讯作者：
Neckers, Len
影响因子：
20.1
作者：
Lima B;Forrester MT;Hess DT;Stamler JS
通讯作者：
Stamler JS