PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury
Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed "parmodulins" that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling through Gβγ, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-κB-mediated transcriptional activation and up-regulation of select cytoprotective transcripts. STC1 is among the up-regulated transcripts, and knockdown of stanniocalin-1 blocks the protective effects of both parmodulins and APC. Induction of this signaling pathway in vivo protects against thromboinflammatory injury in blood vessels. Small-molecule activation of endothelial cytoprotection through PAR1 represents an approach for treatment of thromboinflammatory disease and provides proof-of-principle for the strategy of targeting the cytoplasmic surface of GPCRs to achieve pathway selective signaling.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:115 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 115(2018), 5 vom: 30. Jan., Seite E982-E991 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
De Ceunynck, Karen [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 25.07.2018 Date Revised 13.11.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.1718600115 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM280055706 |
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| 100 | 1 | |a De Ceunynck, Karen |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PAR1 agonists stimulate APC-like endothelial cytoprotection and confer resistance to thromboinflammatory injury |
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| 500 | |a Date Completed 25.07.2018 | ||
| 500 | |a Date Revised 13.11.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in several animal models of disease, and APC has been used clinically in severe sepsis and wound healing. Clinical use of APC, however, is limited by its immunogenicity and its anticoagulant activity. We show that a class of small molecules termed "parmodulins" that act at the cytosolic face of PAR1 stimulates APC-like cytoprotective signaling in endothelium. Parmodulins block thrombin generation in response to inflammatory mediators and inhibit platelet accumulation on endothelium cultured under flow. Evaluation of the antithrombotic mechanism showed that parmodulins induce cytoprotective signaling through Gβγ, activating a PI3K/Akt pathway and eliciting a genetic program that includes suppression of NF-κB-mediated transcriptional activation and up-regulation of select cytoprotective transcripts. STC1 is among the up-regulated transcripts, and knockdown of stanniocalin-1 blocks the protective effects of both parmodulins and APC. Induction of this signaling pathway in vivo protects against thromboinflammatory injury in blood vessels. Small-molecule activation of endothelial cytoprotection through PAR1 represents an approach for treatment of thromboinflammatory disease and provides proof-of-principle for the strategy of targeting the cytoplasmic surface of GPCRs to achieve pathway selective signaling | ||
| 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 PAR1 | |
| 650 | 4 | |a cytoprotection | |
| 650 | 4 | |a endothelium | |
| 650 | 4 | |a inflammation | |
| 650 | 4 | |a thrombosis | |
| 650 | 7 | |a Glycoproteins |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Receptor, PAR-1 |2 NLM | |
| 650 | 7 | |a Receptors, G-Protein-Coupled |2 NLM | |
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| 700 | 1 | |a Peters, Christian G |e verfasserin |4 aut | |
| 700 | 1 | |a Jain, Abhishek |e verfasserin |4 aut | |
| 700 | 1 | |a Higgins, Sarah J |e verfasserin |4 aut | |
| 700 | 1 | |a Aisiku, Omozuanvbo |e verfasserin |4 aut | |
| 700 | 1 | |a Fitch-Tewfik, Jennifer L |e verfasserin |4 aut | |
| 700 | 1 | |a Chaudhry, Sharjeel A |e verfasserin |4 aut | |
| 700 | 1 | |a Dockendorff, Chris |e verfasserin |4 aut | |
| 700 | 1 | |a Parikh, Samir M |e verfasserin |4 aut | |
| 700 | 1 | |a Ingber, Donald E |e verfasserin |4 aut | |
| 700 | 1 | |a Flaumenhaft, Robert |e verfasserin |4 aut | |
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