Skip to content


Open Access

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

  • Sabine Meurer1, 2,
  • Sylke Pioch2,
  • Tatjana Pabst2,
  • Nils Opitz1, 2, 3,
  • Peter M Schmidt1, 4,
  • Tobias Beckhaus5,
  • Kristina Wagner2,
  • Simone Matt2,
  • Kristina Gegenbauer1, 6,
  • Sandra Geschka7, 8,
  • Michael Karas5,
  • Johannes-Peter Stasch7, 9,
  • Harald HHW Schmidt1 and
  • Werner Müller-Esterl2Email author
BMC Pharmacology20099(Suppl 1):P49

Published: 11 August 2009


OxideOxidative StressNitric OxideBlood VesselVascular Disease


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.


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.


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

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


© Meurer et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.