Sabine Meurer, Sylke Pioch, Tatjana Pabst, Nils Opitz, Peter M. Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael Karas, Johannes-Peter Stasch, Harald H. H. W. Schmidt, Werner Müller-Esterl
- Background: Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and down-regulation of its major intracellular receptor, the alpha/beta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of sGC's heme and responsiveness to NO.
Results: sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here we show that oxidation-induced down-regulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand, BAY 58-2667, prevented sGC ubiquitination and stabilized both alpha and beta subunits.
Conclusion: Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.
MetadatenAuthor: | Sabine MeurerGND, Sylke PiochGND, Tatjana Pabst, Nils Opitz, Peter M. Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael KarasGND, Johannes-Peter Stasch, Harald H. H. W. SchmidtGND, Werner Müller-EsterlORCiDGND |
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URN: | urn:nbn:de:hebis:30-70854 |
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DOI: | https://doi.org/10.1186/1471-2210-9-S1-P49 |
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ISSN: | 1471-2210 |
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Parent Title (English): | BMC pharmacology |
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Publisher: | BioMed Central |
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Place of publication: | London |
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Document Type: | Article |
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Language: | English |
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Date of Publication (online): | 2009/09/20 |
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Date of first Publication: | 2009/08/11 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Contributing Corporation: | 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications Regensburg, Germany. 19–21 June 2009 |
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Release Date: | 2009/09/20 |
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Volume: | 9 |
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Issue: | (Suppl 1):P49 |
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Page Number: | 1 |
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First Page: | 1 |
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Last Page: | 1 |
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Note: | © 2009 Meurer et al; licensee BioMed Central Ltd. |
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Source: | BMC Pharmacology 2009, 9(Suppl 1):P49 ; doi:10.1186/1471-2210-9-S1-P49 ; from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications Regensburg, Germany. 19–21 June 2009 |
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HeBIS-PPN: | 219001995 |
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Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
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| Biochemie, Chemie und Pharmazie / Pharmazie |
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| Medizin / Medizin |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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Sammlungen: | Sammlung Biologie / Sondersammelgebiets-Volltexte |
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Licence (German): | Deutsches Urheberrecht |
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