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+
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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Metadaten
Author:Sabine Meurer, Tatjana Pabst, Sylke Pioch, Nils Opitz, Peter M. Schmidt, Kristina Wagner, Simone Matt, Harald HHW Schmidt, Werner Müller-Esterl
URN:urn:nbn:de:hebis:30-47192
Document Type:Article
Language:English
Date of Publication (online):2007/08/06
Year of first Publication:2007
Publishing Institution:Univ.-Bibliothek Frankfurt am Main
Release Date:2007/08/06
Note:
© 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. - BMC Pharmacology 2007, 7(Suppl 1):S34. - http://www.biomedcentral.com/1471-2210/7/S1/S34. - doi:10.1186/1471-2210-7-S1-S34
HeBIS PPN:189555793
Institutes:Biochemie und Chemie
Dewey Decimal Classification:570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Sondersammelgebiets-Volltexte
Licence (German):License Logo Veröffentlichungsvertrag für Publikationen

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