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  Mapping the Endothelial Cell S-Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function

Bibli, S.-I., Hu, J., Looso, M., Weigert, A., Ratiu, C., Wittig, J., et al. (2021). Mapping the Endothelial Cell S-Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function. CIRCULATION, 143(9), 935-948. doi:10.1161/CIRCULATIONAHA.120.051877.

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Bibli, Sofia-Iris, Author
Hu, Jiong, Author
Looso, Mario1, Author           
Weigert, Andreas, Author
Ratiu, Corina, Author
Wittig, Janina, Author
Drekolia, Maria Kyriaki, Author
Tombor, Lukas, Author
Randriamboavonjy, Voahanginirina, Author
Leisegang, Matthias S., Author
Goymann, Philipp1, Author           
Lagos, Fredy Delgado, Author
Fisslthaler, Beate, Author
Zukunft, Sven, Author
Kyselova, Anastasia, Author
Justo, Alberto Fernando Oliveira, Author
Heidler, Juliana, Author
Tsilimigras, Diamantis, Author
Brandes, Ralf P., Author
Dimmeler, Stefanie, Author
Papapetropoulos, Andreas, AuthorKnapp, Stefan, AuthorOffermanns, Stefan2, Author           Wittig, Ilka, AuthorNishimura, Stephen L., AuthorSigala, Fragiska, AuthorFleming, Ingrid, Author more..
1Bioinformatics, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591704              
2Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591696              


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 Abstract: Background: In vascular endothelial cells, cysteine metabolism by the cystathionine gamma lyase (CSE), generates hydrogen sulfide-related sulfane sulfur compounds (H2Sn), that exert their biological actions via cysteine S-sulfhydration of target proteins. This study set out to map the "S-sulfhydrome" (ie, the spectrum of proteins targeted by H2Sn) in human endothelial cells. Methods: Liquid chromatography with tandem mass spectrometry was used to identify S-sulfhydrated cysteines in endothelial cell proteins and beta 3 integrin intraprotein disulfide bond rearrangement. Functional studies included endothelial cell adhesion, shear stress-induced cell alignment, blood pressure measurements, and flow-induced vasodilatation in endothelial cell-specific CSE knockout mice and in a small collective of patients with endothelial dysfunction. Results: Three paired sample sets were compared: (1) native human endothelial cells isolated from plaque-free mesenteric arteries (CSE activity high) and plaque-containing carotid arteries (CSE activity low); (2) cultured human endothelial cells kept under static conditions or exposed to fluid shear stress to decrease CSE expression; and (3) cultured endothelial cells exposed to shear stress to decrease CSE expression and treated with solvent or the slow-releasing H2Sn donor, SG1002. The endothelial cell "S-sulfhydrome" consisted of 3446 individual cysteine residues in 1591 proteins. The most altered family of proteins were the integrins and focusing on beta 3 integrin in detail we found that S-sulfhydration affected intraprotein disulfide bond formation and was required for the maintenance of an extended-open conformation of the beta leg. beta 3 integrin S-sulfhydration was required for endothelial cell mechanotransduction in vitro as well as flow-induced dilatation in murine mesenteric arteries. In cultured cells, the loss of S-sulfhydration impaired interactions between beta 3 integrin and G alpha 13 (guanine nucleotide-binding protein subunit alpha 13), resulting in the constitutive activation of RhoA (ras homolog family member A) and impaired flow-induced endothelial cell realignment. In humans with atherosclerosis, endothelial function correlated with low H2Sn generation, impaired flow-induced dilatation, and failure to detect beta 3 integrin S-sulfhydration, all of which were rescued after the administration of an H2Sn supplement. Conclusions: Vascular disease is associated with marked changes in the S-sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short-term H2Sn supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease.


 Dates: 2020-12-142021-03-02
 Publication Status: Published in print
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Source Genre: Journal
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Pages: - Volume / Issue: 143 (9) Sequence Number: - Start / End Page: 935 - 948 Identifier: ISSN: 0009-7322