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

  • 1, 2,
  • 2,
  • 2,
  • 1, 2, 3,
  • 1, 4,
  • 5,
  • 2,
  • 2,
  • 1, 6,
  • 7, 8,
  • 5,
  • 7, 9,
  • 1 and
  • 2Email author
BMC Pharmacology20099(Suppl 1):P49

https://doi.org/10.1186/1471-2210-9-S1-P49

Published: 11 August 2009

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.

Authors’ Affiliations

(1)
Department of Pharmacology & Centre for Vascular Health, Monash University, Melbourne, Clayton, Australia
(2)
Institute of Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany
(3)
Bayer Schering Pharma AG, Berlin, Germany
(4)
CSIRO Molecular Health Technologies, Parkville, Australia
(5)
Institute of Pharmaceutical Chemistry, University of Frankfurt, Frankfurt, Germany
(6)
Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Ireland
(7)
Cardiovascular Research, Bayer HealthCare AG, Wuppertal, Germany
(8)
Department of Pharmacology, University of Cologne, Cologne, Germany
(9)
School of Pharmacy, Martin-Luther-University, Halle, Germany

Copyright

© Meurer et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

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