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Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteosomal degradation

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BioMed Central

Page 1 of 1

(page number not for citation purposes)

BMC Pharmacology

Open Access

Poster presentation

Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteosomal degradation Sabine Meurer

1,2

, Sylke Pioch

2

, Tatjana Pabst

2

, Nils Opitz

1,2,3

,

Peter M Schmidt

1,4

, Tobias Beckhaus

5

, Kristina Wagner

2

, Simone Matt

2

, Kristina Gegenbauer

1,6

, Sandra Geschka

7,8

, Michael Karas

5

, Johannes- Peter Stasch

7,9

, Harald HHW Schmidt

1

and Werner Müller-Esterl*

2

Address: 1Department of Pharmacology & Centre for Vascular Health, Monash University, Melbourne, Clayton, VIC 3800, Australia, 2Institute of Biochemistry II, University of Frankfurt Medical School, Theodor-Stern-Kai7, 60590 Frankfurt, Germany, 3Bayer Schering Pharma AG, Müllerstr.

178, 13353 Berlin, Germany, 4CSIRO Molecular Health Technologies, 343 Royal Parade, Parkville, VIC 3052, Australia, 5Institute of Pharmaceutical Chemistry, University of Frankfurt, Max von Laue-Str.9, 60439 Frankfurt, Germany, 6Conway Institute of Biomolecular &

Biomedical Research, University College Dublin, Ireland, 7Cardiovascular Research, Bayer HealthCare AG, Aprather Weg 18a, 42069 Wuppertal, Germany, 8Department of Pharmacology, University of Cologne, Gleueler Strasse 24,50931 Cologne, Germany and 9Martin-Luther-University, School of Pharmacy, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany

Email: Werner Müller-Esterl* - praesident@uni-frankfurt.de

* Corresponding author

Background

Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and down- regulation of its major intracellular receptor, the α/β het- erodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of sGC's heme and responsiveness to NO.

Results

sGC activators such as BAY 58-2667 bind to oxidized/

heme-free sGC and reactivate the enzyme to exert disease- specific vasodilation. Here we show that oxidation- induced down-regulation of sGC protein extends to iso- lated blood vessels. Mechanistically, degradation was trig- gered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand, BAY 58-2667, prevented sGC ubiquitination and stabilized both α and β subunits.

Conclusion

Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodi- lators by stabilizing their receptor, oxidized/heme-free sGC.

from 4th International Conference of cGMP Generators, Effectors and Therapeutic Implications Regensburg, Germany. 19–21 June 2009

Published: 11 August 2009

BMC Pharmacology 2009, 9(Suppl 1):P49 doi:10.1186/1471-2210-9-S1-P49

<supplement> <title> <p>4th International Conference of cGMP Generators, Effectors and Therapeutic Implications</p> </title> <note>Meeting abstracts – A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1471-2210-9-S1-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1471-2210-9-S1-info.pdf</url> </supplement>

This abstract is available from: http://www.biomedcentral.com/1471-2210/9/S1/P49

© 2009 Meurer et al; licensee BioMed Central Ltd.

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