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 

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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