TY - JOUR
TI - Mapping the Endothelial Cell S -Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function
AU - Bibli, S.-I.
AU - Hu, J.
AU - Looso, M.
AU - Weigert, A.
AU - Ratiu, C.
AU - Wittig, J.
AU - Drekolia, M.K.
AU - Tombor, L.
AU - Randriamboavonjy, V.
AU - Leisegang, M.S.
AU - Goymann, P.
AU - Delgado Lagos, F.
AU - Fisslthaler, B.
AU - Zukunft, S.
AU - Kyselova, A.
AU - Justo, A.F.O.
AU - Heidler, J.
AU - Tsilimigras, D.
AU - Brandes, R.P.
AU - Dimmeler, S.
AU - Papapetropoulos, A.
AU - Knapp, S.
AU - Offermanns, S.
AU - Wittig, I.
AU - Nishimura, S.L.
AU - Sigala, F.
AU - Fleming, I.
JO - CIRCULATION
PY - 2021
VL - null
TODO - null
SP - 935-948
PB - Lippincott Williams and Wilkins
SN - 0009-7322
TODO - 10.1161/CIRCULATIONAHA.120.051877
TODO - beta integrin;  cystathionine gamma lyase;  cysteine;  disulfide;  hydrogen sulfide;  RhoA guanine nucleotide binding protein;  thiol derivative, animal;  chemistry;  cytology;  drug effect;  endothelium cell;  genetics;  high performance liquid chromatography;  human;  mechanotransduction;  metabolism;  mouse;  shear strength;  tandem mass spectrometry;  vasodilatation, Animals;  Chromatography, High Pressure Liquid;  Cystathionine gamma-Lyase;  Cysteine;  Disulfides;  Endothelial Cells;  Humans;  Hydrogen Sulfide;  Integrin beta Chains;  Mechanotransduction, Cellular;  Mice;  rhoA GTP-Binding Protein;  Shear Strength;  Sulfhydryl Compounds;  Tandem Mass Spectrometry;  Vasodilation
TODO - Background: In vascular endothelial cells, cysteine metabolism by the cystathionine γ 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 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 H2Sndonor, 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 H2Sngeneration, impaired flow-induced dilatation, and failure to detect β3 integrin S-sulfhydration, all of which were rescued after the administration of an H2Snsupplement. Conclusions: Vascular disease is associated with marked changes in the S-sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short-term H2Snsupplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease. © 2021 Lippincott Williams and Wilkins. All rights reserved.
ER -