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dc.creatorZhao, Shuang
dc.creatorTang, Xin
dc.creatorMiao, Zian
dc.creatorChen, Yurong
dc.creatorCao, Jiawei
dc.creatorSong, Tianyu
dc.creatorYou, Daiting
dc.creatorZhong, Yanqing
dc.creatorLin, Zhe
dc.creatorWang, Dan
dc.creatorShi, Zhiguang
dc.creatorTang, Xinlong
dc.creatorWang, Dongjin
dc.creatorChen, Shaoliang
dc.creatorWang, Liansheng
dc.creatorGu, Aihua
dc.creatorChen, Feng
dc.creatorXie, Liping
dc.creatorHuang, Zhengrong
dc.creatorWang, Hong
dc.creatorJi, Yong
dc.description.abstractEndothelial 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.
dc.format.extent12 pages
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartRedox Biology, Vol. 52
dc.rightsAttribution-NonCommercial-NoDerivs CC BY-NC-ND
dc.subjectHeat shock protein 90
dc.subjectOxidative stress
dc.subjectEndothelial dysfunction
dc.titleHsp90 S-nitrosylation at Cys521, as a conformational switch, modulates cycling of Hsp90-AHA1-CDC37 chaperone machine to aggravate atherosclerosis
dc.type.genreJournal article
dc.contributor.groupCenter for Metabolic Disease Research (Temple University)
dc.contributor.groupCardiovascular Research Center (Temple University)
dc.contributor.groupSol Sherry Thrombosis Research Center (Temple University)
dc.description.departmentCardiovascular Sciences
dc.description.departmentMicrobiology, Immunology and Inflammation
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact
dc.description.schoolcollegeLewis Katz School of Medicine
dc.temple.creatorWang, Hong

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