title: Regulation of vascular guanylyl cyclase by endothelial nitric oxide-dependent posttranslational modification.
abstract: In isolated cells, soluble guanylyl cyclase (sGC) activity is regulated by exogenous nitric oxide (NO) via downregulation of expression and posttranslational S-nitrosylation. The aim of this study was to investigate whether such regulatory mechanism impact on endothelium-dependent vasodilation in a newly developed mouse strain carrying an endothelial-specific overexpression of eNOS (eNOS(++)). When compared with transgene negative controls (eNOS(n)), eNOS(++)-mice showed a 3.3-fold higher endothelial-specific aortic eNOS expression, increased vascular cGMP and VASP phosphorylation, a L-nitroarginine (L-NA)-inhibitable decrease in systolic blood pressure, but normal levels of peroxynitrite and nitrotyrosine formation, endothelium-dependent aortic vasodilation and vasodilation to NO donors. Western blot analysis for sGC showed similar protein levels of sGC-α1 and sGC-β1 subunits in eNOS(n) and eNOS(++). In striking contrast, the activity of isolated sGC was strongly decreased in lungs of eNOS(++). Semiquantitative evaluation of sGC-β1-S-nitrosylation demonstrated that this loss of sGC activity is associated with increased nitrosylation of the enzyme in eNOS(++), a difference that disappeared after L-NA-treatment. Our data suggest the existence of a physiologic NO-dependent posttranslational regulation of vascular sGC in mammals involving S-nitrosylation as a key mechanism. Because this mechanism can compensate for reduction in vascular NO bioavailability, it may mask the development of endothelial dysfunction.
authors.affiliation: Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-University, Moorenstrasse 5, Düsseldorf, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Oppermann
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Suvorava
authors.forename: Till
authors.initials: T
authors.lastname: Freudenberger
authors.forename: Vu Thao-Vi
authors.initials: VT
authors.lastname: Dao
authors.forename: Jens W
authors.initials: JW
authors.lastname: Fischer
authors.forename: Martina
authors.initials: M
authors.lastname: Weber
authors.forename: Georg
authors.initials: G
authors.lastname: Kojda
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D006834:Hydrazines; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D006152:Cyclic GMP