Volume 7 Supplement 1

3rd International Conference on cGMP Generators, Effectors and Therapeutic Implications

Open Access

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

  • Sabine Meurer1, 2,
  • Tatjana Pabst1,
  • Sylke Pioch1,
  • Nils Opitz1, 2,
  • Peter M Schmidt2,
  • Kristina Wagner1,
  • Simone Matt1,
  • Harald HHW Schmidt2 and
  • Werner Müller-Esterl1Email author
BMC Pharmacology20077(Suppl 1):S34

https://doi.org/10.1186/1471-2210-7-S1-S34

Published: 25 July 2007

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.

Authors’ Affiliations

(1)
Institute of Biochemistry II, University of Frankfurt Medical School
(2)
Department of Pharmacology & Centre for Vascular Health, Monash University

Copyright

© Meurer et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

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