title: Redox regulation of soluble epoxide hydrolase by 15-deoxy-delta-prostaglandin J2 controls coronary hypoxic vasodilation.
abstract: BACKGROUND
  15-Deoxy-Δ-prostaglandin (15d-PG)J(2) is an electrophilic oxidant that dilates the coronary vasculature. This lipid can adduct to redox active protein thiols to induce oxidative posttranslational modifications that modulate protein and tissue function.
  
  
  OBJECTIVE
  To investigate the role of oxidative protein modifications in 15d-PGJ(2)-mediated coronary vasodilation and define the distal signaling pathways leading to enhanced perfusion.
  
  
  RESULTS
  Proteomic screening with biotinylated 15d-PGJ(2) identified novel vascular targets to which it adducts, most notably soluble epoxide hydrolase (sEH). 15d-PGJ(2) inhibited sEH by specifically adducting to a highly conserved thiol (Cys521) adjacent to the catalytic center of the hydrolase. Indeed a Cys521Ser sEH "redox-dead" mutant was resistant to 15d-PGJ(2)-induced hydrolase inhibition. 15d-PGJ(2) dilated coronary vessels and a role for hydrolase inhibition was supported by 2 structurally different sEH antagonists each independently inducing vasorelaxation. Furthermore, 15d-PGJ(2) and sEH antagonists also increased coronary effluent epoxyeicosatrienoic acids consistent with their vasodilatory actions. Indeed 14,15-EET alone induced relaxation and 15d-PGJ(2)-mediated vasodilation was blocked by the EET receptor antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE). Additionally, the coronary vasculature of sEH-null mice was basally dilated compared to wild-type controls and failed to vasodilate in response to 15d-PGJ(2). Coronary vasodilation to hypoxia in wild-types was accompanied by 15d-PGJ(2) adduction to and inhibition of sEH. Consistent with the importance of hydrolase inhibition, sEH-null mice failed to vasodilate during hypoxia.
  
  
  CONCLUSIONS
  This represents a new paradigm for the regulation of sEH by an endogenous lipid, which is integral to the fundamental physiological response of coronary hypoxic vasodilation.
authors.affiliation: King's College London, Cardiovascular Division, The Rayne Institute, St Thomas Hospital, London, SE1 7EH, United Kingdom.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Charles
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Burgoyne
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.forename: Steven M
authors.initials: SM
authors.lastname: Weldon
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Aimee
authors.initials: A
authors.lastname: Landar
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004851:Epoxide Hydrolases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014664:Vasodilation / Q000502:physiology*
chemical_list: C477819:15-deoxyprostaglandin J2; D004851:Epoxide Hydrolases; D015230:Prostaglandin D2