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BMC Pharmacology

, 7:S34 | Cite as

Oxidative stress induces CHIP-mediated ubiquitination and roteasomal degradation of soluble guanylyl cyclase

  • Sabine Meurer
  • Tatjana Pabst
  • Sylke Pioch
  • Nils Opitz
  • Peter M Schmidt
  • Kristina Wagner
  • Simone Matt
  • Harald HHW Schmidt
  • Werner Müller-Esterl
Open Access
Oral presentation

Keywords

Oxidative Stress Protein Level Mammalian Cell Deleterious Effect Vascular System 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Oxidative stress attenuates the NO-cGMP pathway, e.g. in the vascular system, through scavenging of free NO radicals by superoxide O2•-, by inactivation of soluble guanylyl cyclase (sGC) via oxidation of its central Fe2+ ion, and by down-regulation of sGC protein levels. While the former pathways are well established, the molecular mechanisms underlying the latter are still obscure. Using oxidative sGC inhibitor ODQ we demonstrate rapid down-regulation of sGC protein in mammalian cells. Co-incubation with proteasomal inhibitor MG132 results in accumulation of ubiquitinated sGC whereas sGC activator BAY 58–2667 prevents ubiquitination. ODQ-induced down-regulation of sGC is mediated through selective ubiquitination of its b subunit, and BAY 58–2667 abrogates this effect. Ubiquitination of sGC-b is dramatically enhanced by E3 ligase CHIP. Our data indicate that oxidative stress promotes ubiquitination of sGC b subunit through E3 ligase CHIP, and that sGC activator 58–2667 reverts this effect, most likely through stabilization of the heme-free b subunit. Thus the deleterious effects of oxidative stress can be counter-balanced by an activator of a key enzyme of vascular homeostasis.

Copyright information

© Meurer et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

Authors and Affiliations

  • Sabine Meurer
    • 1
    • 2
  • Tatjana Pabst
    • 1
  • Sylke Pioch
    • 1
  • Nils Opitz
    • 1
    • 2
  • Peter M Schmidt
    • 2
  • Kristina Wagner
    • 1
  • Simone Matt
    • 1
  • Harald HHW Schmidt
    • 2
  • Werner Müller-Esterl
    • 1
  1. 1.Institute of Biochemistry IIUniversity of Frankfurt Medical SchoolTheodor-Stern-Kai 7Germany
  2. 2.Department of Pharmacology & Centre for Vascular HealthMonash UniversityClaytonAustralia

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