title: Characterization of the function of cytoglobin as an oxygen-dependent regulator of nitric oxide concentration.
abstract: The endogenous vasodilator nitric oxide (NO) is metabolized in tissues in an O(2)-dependent manner. This regulates NO levels in the vascular wall; however, the underlying molecular basis of this O(2)-dependent NO consumption remains unclear. While cytoglobin (Cygb) was discovered a decade ago, its physiological function remains uncertain. Cygb is expressed in the vascular wall and can consume NO in an O(2)-dependent manner. Therefore, we characterize the process of the O(2)-dependent consumption of NO by Cygb in the presence of the cellular reductants and reducing systems ascorbate (Asc) and cytochrome P(450) reductase (CPR), measure rate constants of Cygb reduction by Asc and CPR, and propose a reaction mechanism and derive a related kinetic model for this O(2)-dependent NO consumption involving Cygb(Fe(3+)) as the main intermediate reduced back to ferrous Cygb by cellular reductants. This kinetic model expresses the relationship between the rate of O(2)-dependent consumption of NO by Cygb and rate constants of the molecular reactions involved. The predicted rate of O(2)-dependent consumption of NO by Cygb is consistent with experimental results supporting the validity of the kinetic model. Simulations based on this kinetic model suggest that the high efficiency of Cygb in regulating the NO consumption rate is due to the rapid reduction of Cygb by cellular reductants, which greatly increases the rate of consumption of NO at higher O(2) concentrations, and binding of NO to Cygb, which reduces the rate of consumption of NO at lower O(2) concentrations. Thus, the coexistence of Cygb with efficient reductants in tissues allows Cygb to function as an O(2)-dependent regulator of NO decay.
authors.affiliation: Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, 473 West 12th Avenue, Columbus, Ohio 43210, USA. xiaoping.liu@osumc.edu
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Liu
authors.forename: Douglas
authors.initials: D
authors.lastname: Follmer
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Zweier
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Craig
authors.initials: C
authors.lastname: Hemann
authors.forename: Kerui
authors.initials: K
authors.lastname: Liu
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Druhan
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D000078842:Cytoglobin; D005914:Globins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009569:Nitric Oxide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010100:Oxygen / Q000737:chemistry / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D019163:Reducing Agents / Q000737:chemistry / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet
chemical_list: C000627265:CYGB protein, human; D000078842:Cytoglobin; D019163:Reducing Agents; D009569:Nitric Oxide; D005914:Globins; D010100:Oxygen