Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteasomal degradation.
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.
Meurer
Sabine
S
Department of Pharmacology & Centre for Vascular Health, University of Frankfurt, Germany.
Pioch
Sylke
S
Pabst
Tatjana
T
Opitz
Nils
N
Schmidt
Peter M
PM
Beckhaus
Tobias
T
Wagner
Kristina
K
Matt
Simone
S
Gegenbauer
Kristina
K
Geschka
Sandra
S
Karas
Michael
M
Stasch
Johannes-Peter
JP
Schmidt
Harald H H W
HH
Müller-Esterl
Werner
W
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*
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