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

Sabine Meurer, Sylke Pioch, Tatjana Pabst, Nils Opitz, Peter Manuel Schmidt, Tobias Beckhaus, Kristina Wagner, Simone Matt, Kristina Gegenbauer, Sandra Geschka, Michael Karas, Johannes-Peter Stasch, Harald H H W Schmidt, Werner Muller-Esterl

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Abstract

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 alphabeta 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 alpha and beta 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.
Original languageEnglish
Pages (from-to)33 - 41
Number of pages9
JournalCirculation Research
Volume105
Issue number1
DOIs
Publication statusPublished - 2009

Cite this

Meurer, S., Pioch, S., Pabst, T., Opitz, N., Schmidt, P. M., Beckhaus, T., Wagner, K., Matt, S., Gegenbauer, K., Geschka, S., Karas, M., Stasch, J-P., Schmidt, H. H. H. W., & Muller-Esterl, W. (2009). Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteasomal degradation. Circulation Research, 105(1), 33 - 41. https://doi.org/10.1186/1471-2210-9-S1-P49