Published online before print May 28, 2009, doi: 10.1161/CIRCRESAHA.109.198234
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Submitted on August 31, 2007
Revised on May 10, 2009
Accepted on May 14, 2009
Nitric Oxide–Independent Vasodilator Rescues Heme-Oxidized Soluble Guanylate Cyclase From Proteasomal Degradation
Sabine Meurer ;
From the Department of Pharmacology & Centre for Vascular Health (S. Meurer, N.O., P.M.S., K.G., H.H.H.W.S.), Monash University, Melbourne, Clayton, Australia; Institute of Biochemistry II (S.M., S.P., T.P., N.O., K.W., S. Matt, W.M.-E.), University of Frankfurt Medical School, Germany; Institute of Pharmaceutical Chemistry (T.B., M.K.), University of Frankfurt, Germany; Institute of Cardiovascular Research (S.G., J.-P.S.), Bayer HealthCare AG, Wuppertal, Germany; School of Pharmacy (J.-P.S.), Martin-Luther-University, Halle, Germany; and Department of Pharmacology (S.G.), University of Cologne, Germany.
* To whom correspondence should be addressed. E-mail: wme{at}biochem2.de.
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 downregulation of its major intracellular receptor, the 
heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of the heme of sGC, as well as the responsiveness of sGC to NO. 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 downregulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand BAY 58-2667 prevented sGC ubiquitination and stabilized both and subunits. 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 vasodilators by stabilizing their receptor, oxidized/heme-free sGC.
Key words: soluble guanylate cyclase • nitric oxide • ubiquitination • proteasome • BAY 58-2667
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