Mapping the Endothelial Cell S -Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function
| Autor: | Mario Looso, Stefan Offermanns, Lukas Tombor, Voahanginirina Randriamboavonjy, Philipp Goymann, Anastasia Kyselova, Stephen L. Nishimura, Stefanie Dimmeler, Alberto Fernando Oliveira Justo, Matthias S. Leisegang, Sven Zukunft, Andreas Weigert, Andreas Papapetropoulos, Beate Fisslthaler, Sofia-Iris Bibli, Juliana Heidler, Janina Wittig, Ingrid Fleming, Corina Ratiu, Jiong Hu, Fragiska Sigala, Diamantis I. Tsilimigras, Stefan Knapp, Fredy Delgado Lagos, Ralf P. Brandes, Ilka Wittig, Maria Kyriaki Drekolia |
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| Rok vydání: | 2021 |
| Předmět: |
0303 health sciences
biology business.industry Hydrogen sulfide Cystathionine gamma-lyase Integrin Cystathionine beta synthase Cell biology Endothelial stem cell 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry Physiology (medical) biology.protein Medicine Mechanotransduction Cardiology and Cardiovascular Medicine business 030217 neurology & neurosurgery Cysteine metabolism 030304 developmental biology Cysteine |
| Zdroj: | Circulation. 143:935-948 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background: In vascular endothelial cells, cysteine metabolism by the cystathionine γ lyase (CSE), generates hydrogen sulfide–related sulfane sulfur compounds (H 2 S n ), 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 H 2 S n ) in human endothelial cells. Methods: Liquid chromatography with tandem mass spectrometry was used to identify S -sulfhydrated cysteines in endothelial cell proteins and β3 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 H 2 S n 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 β3 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 β leg. β3 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 β3 integrin and Gα13 (guanine nucleotide-binding protein subunit α 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 H 2 S n generation, impaired flow-induced dilatation, and failure to detect β3 integrin S -sulfhydration, all of which were rescued after the administration of an H 2 S n 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 H 2 S n supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease. |
| Databáze: | OpenAIRE |
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