Sulfenylation links oxidative stress to protein disulfide isomerase oxidase activity and thrombus formation
Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved..
BACKGROUND: Oxidative stress contributes to thrombosis in atherosclerosis, inflammation, infection, aging, and malignancy. Oxidant-induced cysteine modifications, including sulfenylation, can act as a redox-sensitive switch that controls protein function. Protein disulfide isomerase (PDI) is a prothrombotic enzyme with exquisitely redox-sensitive active-site cysteines.
OBJECTIVES: We hypothesized that PDI is sulfenylated during oxidative stress, contributing to the prothrombotic potential of PDI.
METHODS: Biochemical and enzymatic assays using purified proteins, platelet and endothelial cell assays, and in vivo murine thrombosis studies were used to evaluate the role of oxidative stress in PDI sulfenylation and prothrombotic activity.
RESULTS: PDI exposure to oxidants resulted in the loss of PDI reductase activity and simultaneously promoted sulfenylated PDI generation. Following exposure to oxidants, sulfenylated PDI spontaneously converted to disulfided PDI. PDI oxidized in this manner was able to transfer disulfides to protein substrates. Inhibition of sulfenylation impaired disulfide formation by oxidants, indicating that sulfenylation is an intermediate during PDI oxidation. Agonist-induced activation of platelets and endothelium resulted in the release of sulfenylated PDI. PDI was also sulfenylated by oxidized low-density lipoprotein (oxLDL). In an in vivo model of thrombus formation, oxLDL markedly promoted platelet accumulation following an arteriolar injury. PDI oxidoreductase inhibition blocked oxLDL-mediated augmentation of thrombosis.
CONCLUSION: PDI sulfenylation is a critical posttranslational modification that is an intermediate during disulfide PDI formation in the setting of oxidative stress. Oxidants generated by vascular cells during activation promote PDI sulfenylation, and interference with PDI during oxidative stress impairs thrombus formation.
| Errataetall: |
CommentIn: J Thromb Haemost. 2023 Aug;21(8):2054-2057. - PMID 37468176 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:21 |
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| Enthalten in: |
Journal of thrombosis and haemostasis : JTH - 21(2023), 8 vom: 08. Aug., Seite 2137-2150 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Moua [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 28.07.2023 Date Revised 21.11.2023 published: Print-Electronic CommentIn: J Thromb Haemost. 2023 Aug;21(8):2054-2057. - PMID 37468176 Citation Status MEDLINE |
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| doi: |
10.1016/j.jtha.2023.03.034 |
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| PPN (Katalog-ID): |
NLM35541970X |
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| 100 | 1 | |a Yang, Moua |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Sulfenylation links oxidative stress to protein disulfide isomerase oxidase activity and thrombus formation |
| 264 | 1 | |c 2023 | |
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| 500 | |a Date Completed 28.07.2023 | ||
| 500 | |a Date Revised 21.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: J Thromb Haemost. 2023 Aug;21(8):2054-2057. - PMID 37468176 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a BACKGROUND: Oxidative stress contributes to thrombosis in atherosclerosis, inflammation, infection, aging, and malignancy. Oxidant-induced cysteine modifications, including sulfenylation, can act as a redox-sensitive switch that controls protein function. Protein disulfide isomerase (PDI) is a prothrombotic enzyme with exquisitely redox-sensitive active-site cysteines | ||
| 520 | |a OBJECTIVES: We hypothesized that PDI is sulfenylated during oxidative stress, contributing to the prothrombotic potential of PDI | ||
| 520 | |a METHODS: Biochemical and enzymatic assays using purified proteins, platelet and endothelial cell assays, and in vivo murine thrombosis studies were used to evaluate the role of oxidative stress in PDI sulfenylation and prothrombotic activity | ||
| 520 | |a RESULTS: PDI exposure to oxidants resulted in the loss of PDI reductase activity and simultaneously promoted sulfenylated PDI generation. Following exposure to oxidants, sulfenylated PDI spontaneously converted to disulfided PDI. PDI oxidized in this manner was able to transfer disulfides to protein substrates. Inhibition of sulfenylation impaired disulfide formation by oxidants, indicating that sulfenylation is an intermediate during PDI oxidation. Agonist-induced activation of platelets and endothelium resulted in the release of sulfenylated PDI. PDI was also sulfenylated by oxidized low-density lipoprotein (oxLDL). In an in vivo model of thrombus formation, oxLDL markedly promoted platelet accumulation following an arteriolar injury. PDI oxidoreductase inhibition blocked oxLDL-mediated augmentation of thrombosis | ||
| 520 | |a CONCLUSION: PDI sulfenylation is a critical posttranslational modification that is an intermediate during disulfide PDI formation in the setting of oxidative stress. Oxidants generated by vascular cells during activation promote PDI sulfenylation, and interference with PDI during oxidative stress impairs thrombus formation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a cysteine | |
| 650 | 4 | |a disulfide | |
| 650 | 4 | |a oxidation-reduction | |
| 650 | 4 | |a protein disulfide isomerase | |
| 650 | 4 | |a sulfenylation | |
| 650 | 4 | |a thrombosis | |
| 650 | 7 | |a Cysteine |2 NLM | |
| 650 | 7 | |a K848JZ4886 |2 NLM | |
| 650 | 7 | |a Disulfides |2 NLM | |
| 650 | 7 | |a Oxidants |2 NLM | |
| 650 | 7 | |a Oxidoreductases |2 NLM | |
| 650 | 7 | |a EC 1.- |2 NLM | |
| 650 | 7 | |a Protein Disulfide-Isomerases |2 NLM | |
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| 700 | 1 | |a Chiu, Joyce |e verfasserin |4 aut | |
| 700 | 1 | |a Scartelli, Christina |e verfasserin |4 aut | |
| 700 | 1 | |a Ponzar, Nathan |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Sachin |e verfasserin |4 aut | |
| 700 | 1 | |a Patel, Anika |e verfasserin |4 aut | |
| 700 | 1 | |a Ferreira, Renan B |e verfasserin |4 aut | |
| 700 | 1 | |a Keyes, Robert F |e verfasserin |4 aut | |
| 700 | 1 | |a Carroll, Kate S |e verfasserin |4 aut | |
| 700 | 1 | |a Pozzi, Nicola |e verfasserin |4 aut | |
| 700 | 1 | |a Hogg, Philip J |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Brian C |e verfasserin |4 aut | |
| 700 | 1 | |a Flaumenhaft, Robert |e verfasserin |4 aut | |
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