BMC Pharmacology

, 9:P49 | Cite as

Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteosomal degradation

  • 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 HHW Schmidt
  • Werner Müller-Esterl
Open Access
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Keywords

Oxide Oxidative Stress Nitric Oxide Blood Vessel Vascular Disease 

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 α/β 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 α and β 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.

Copyright information

© Meurer et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

Authors and Affiliations

  • Sabine Meurer
    • 1
    • 2
  • Sylke Pioch
    • 2
  • Tatjana Pabst
    • 2
  • Nils Opitz
    • 1
    • 2
    • 3
  • Peter M Schmidt
    • 1
    • 4
  • Tobias Beckhaus
    • 5
  • Kristina Wagner
    • 2
  • Simone Matt
    • 2
  • Kristina Gegenbauer
    • 1
    • 6
  • Sandra Geschka
    • 7
    • 8
  • Michael Karas
    • 5
  • Johannes-Peter Stasch
    • 7
    • 9
  • Harald HHW Schmidt
    • 1
  • Werner Müller-Esterl
    • 2
  1. 1.Department of Pharmacology & Centre for Vascular HealthMonash UniversityMelbourne, ClaytonAustralia
  2. 2.Institute of Biochemistry IIUniversity of Frankfurt Medical SchoolFrankfurtGermany
  3. 3.Bayer Schering Pharma AGBerlinGermany
  4. 4.CSIRO Molecular Health TechnologiesParkvilleAustralia
  5. 5.Institute of Pharmaceutical ChemistryUniversity of FrankfurtFrankfurtGermany
  6. 6.Conway Institute of Biomolecular & Biomedical ResearchUniversity College DublinIreland
  7. 7.Cardiovascular ResearchBayer HealthCare AGWuppertalGermany
  8. 8.Department of PharmacologyUniversity of CologneCologneGermany
  9. 9.School of PharmacyMartin-Luther-UniversityHalleGermany

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