title: Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteasomal degradation.
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.
authors.affiliation: Department of Pharmacology & Centre for Vascular Health, University of Frankfurt, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Meurer
authors.forename: Sylke
authors.initials: S
authors.lastname: Pioch
authors.forename: Tatjana
authors.initials: T
authors.lastname: Pabst
authors.forename: Nils
authors.initials: N
authors.lastname: Opitz
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schmidt
authors.forename: Tobias
authors.initials: T
authors.lastname: Beckhaus
authors.forename: Kristina
authors.initials: K
authors.lastname: Wagner
authors.forename: Simone
authors.initials: S
authors.lastname: Matt
authors.forename: Kristina
authors.initials: K
authors.lastname: Gegenbauer
authors.forename: Sandra
authors.initials: S
authors.lastname: Geschka
authors.forename: Michael
authors.initials: M
authors.lastname: Karas
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.forename: Harald H H W
authors.initials: HH
authors.lastname: Schmidt
authors.forename: Werner
authors.initials: W
authors.lastname: Müller-Esterl
mesh_terms: D001808:Blood Vessels; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006801:Humans; D009569:Nitric Oxide / Q000494:pharmacology*; D010084:Oxidation-Reduction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D054875:Ubiquitination; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D009569:Nitric Oxide; D006418:Heme; D046988:Proteasome Endopeptidase Complex; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP