{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T13:58:34Z","timestamp":1789826314722,"version":"4.0.1"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2021,3,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      In vascular endothelial cells, cysteine metabolism by the cystathionine \u03b3 lyase (CSE), generates hydrogen sulfide\u2013related sulfane sulfur compounds (H\n                      <jats:sub>2<\/jats:sub>\n                      S\n                      <jats:sub>n<\/jats:sub>\n                      ), that exert their biological actions via cysteine\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydration of target proteins. This study set out to map the \u201c\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydrome\u201d (ie, the spectrum of proteins targeted by H\n                      <jats:sub>2<\/jats:sub>\n                      S\n                      <jats:sub>n<\/jats:sub>\n                      ) in human endothelial cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      Liquid chromatography with tandem mass spectrometry was used to identify\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydrated cysteines in endothelial cell proteins and \u03b23 integrin intraprotein disulfide bond rearrangement. Functional studies included endothelial cell adhesion, shear stress\u2013induced cell alignment, blood pressure measurements, and flow-induced vasodilatation in endothelial cell\u2013specific CSE knockout mice and in a small collective of patients with endothelial dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sub>2<\/jats:sub>\n                      S\n                      <jats:sub>n<\/jats:sub>\n                      donor, SG1002. The endothelial cell \u201c\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydrome\u201d consisted of 3446 individual cysteine residues in 1591 proteins. The most altered family of proteins were the integrins and focusing on \u03b23 integrin in detail we found that\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydration affected intraprotein disulfide bond formation and was required for the maintenance of an extended-open conformation of the \u03b2 leg. \u03b23 integrin\n                      <jats:italic>S<\/jats:italic>\n                      -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\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydration impaired interactions between \u03b23 integrin and G\u03b113 (guanine nucleotide-binding protein subunit \u03b1 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\n                      <jats:sub>2<\/jats:sub>\n                      S\n                      <jats:sub>n<\/jats:sub>\n                      generation, impaired flow-induced dilatation, and failure to detect \u03b23 integrin\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydration, all of which were rescued after the administration of an H\n                      <jats:sub>2<\/jats:sub>\n                      S\n                      <jats:sub>n<\/jats:sub>\n                      supplement.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Vascular disease is associated with marked changes in the\n                      <jats:italic>S<\/jats:italic>\n                      -sulfhydration of endothelial cell proteins involved in mediating responses to flow. Short-term H\n                      <jats:sub>2<\/jats:sub>\n                      S\n                      <jats:sub>n<\/jats:sub>\n                      supplementation improved vascular reactivity in humans highlighting the potential of interfering with this pathway to treat vascular disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.120.051877","type":"journal-article","created":{"date-parts":[[2020,12,14]],"date-time":"2020-12-14T05:02:18Z","timestamp":1607922138000},"page":"935-948","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":108,"title":["Mapping the Endothelial Cell\n                    <i>S<\/i>\n                    -Sulfhydrome Highlights the Crucial Role of Integrin Sulfhydration in Vascular Function"],"prefix":"10.1161","volume":"143","author":[{"given":"Sofia-Iris","family":"Bibli","sequence":"first","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8266-0886","authenticated-orcid":true,"given":"Jiong","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Looso","sequence":"additional","affiliation":[{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."},{"name":"Bioinformatics Core Unit (M.L., P.G.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Weigert","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Germany (A.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7429-0862","authenticated-orcid":true,"given":"Corina","family":"Ratiu","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine, Institute for Cardiovascular Physiology (C.R., M.S.L., R.P.B.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janina","family":"Wittig","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Kyriaki","family":"Drekolia","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Tombor","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Regeneration (L.T., S.D.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3542-6672","authenticated-orcid":true,"given":"Voahanginirina","family":"Randriamboavonjy","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6084-6484","authenticated-orcid":true,"given":"Matthias S.","family":"Leisegang","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine, Institute for Cardiovascular Physiology (C.R., M.S.L., R.P.B.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Goymann","sequence":"additional","affiliation":[{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."},{"name":"Bioinformatics Core Unit (M.L., P.G.), Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredy","family":"Delgado Lagos","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Fisslthaler","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Zukunft","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Kyselova","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5531-0485","authenticated-orcid":true,"given":"Alberto Fernando Oliveira","family":"Justo","sequence":"additional","affiliation":[{"name":"Institute for Vascular Signalling (S-I.B., J.H., J.W., M.K.D., V.R., F.D.L., B.F., S.Z., A.K., A.F.O.J., I.F.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Heidler","sequence":"additional","affiliation":[{"name":"Functional Proteomics (J.Heidler., I.W.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diamantis","family":"Tsilimigras","sequence":"additional","affiliation":[{"name":"First Propedeutic Department of Surgery, Vascular Surgery Division (D.T., F.S.), National and Kapodistrian University of Athens Medical School, Greece."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-0048","authenticated-orcid":true,"given":"Ralf P.","family":"Brandes","sequence":"additional","affiliation":[{"name":"Centre for Molecular Medicine, Institute for Cardiovascular Physiology (C.R., M.S.L., R.P.B.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1045-2436","authenticated-orcid":true,"given":"Stefanie","family":"Dimmeler","sequence":"additional","affiliation":[{"name":"Institute for Cardiovascular Regeneration (L.T., S.D.), Goethe University, Frankfurt am Main, Germany."},{"name":"German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany (S-I.B., J.Hu, M.L., C.R., J.W., L.T., V.R., M.S.L., P.G., F.D.L., B.F., S.Z., A.K., A.F.O.J., J.Heidler, R.P.B., S.D., S.O., I.W., I.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Papapetropoulos","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy (A.P.), National and Kapodistrian University of Athens Medical School, Greece."},{"name":"Clinical, Experimental Surgery and Translational Research Center, Biomedical Research Foundation of the Academy of Athens, Greece (A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Knapp","sequence":"additional","affiliation":[{"name":"Institute for Pharmaceutical Chemistry and Buchmann Institute for Molecular Life Sciences (S.K.), 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