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

  • 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.

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Author:Sabine MeurerGND, Tatjana Pabst, Sylke PiochGND, Nils Opitz, Peter M. Schmidt, Kristina Wagner, Simone Matt, Harald H. H. W. SchmidtGND, Werner Müller-EsterlORCiDGND
Parent Title (English):BMC pharmacology
Document Type:Article
Date of Publication (online):2007/07/25
Date of first Publication:2007/07/25
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2007/08/06
Volume:7(Suppl 1)
Page Number:1
First Page:1
Last Page:1
© 2007 Meurer et al; licensee BioMed Central Ltd.
Source:3. International Conference on cGMP Generators, Effectors and Therapeutic Implications : Dresden, Germany, 15 – 17 June 2007. - http://www.biomedcentral.com/1471-2210/7/S1/S34
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Sammlung Biologie / Sondersammelgebiets-Volltexte
Licence (German):License LogoDeutsches Urheberrecht