Redox regulation of soluble epoxide hydrolase by 15-Deoxy-Δ- Prostaglandin J2 Controls coronary hypoxic vasodilation

Rebecca L. Charles, Joseph R. Burgoyne, Manuel Mayr, Steven M. Weldon, Norbert Hubner, Hua Dong, Christophe Morisseau, Bruce D. Hammock, Aimee Landar, Philip Eaton

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Rationale: 15-Deoxy-Δ-prostaglandin (15d-PG)J2 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. Methods and Results: Proteomic screening with biotinylated 15d-PGJ2 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-PGJ2-induced hydrolase inhibition. 15d-PGJ2 dilated coronary vessels and a role for hydrolase inhibition was supported by 2 structurally different sEH antagonists each independently inducing vasorelaxation. Furthermore, 15d-PGJ2 and sEH antagonists also increased coronary effluent epoxyeicosatrienoic acids consistent with their vasodilatory actions. Indeed 14,15-EET alone induced relaxation and 15d-PGJ2-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-PGJ2. Coronary vasodilation to hypoxia in wild-types was accompanied by 15d-PGJ2 adduction to and inhibition of sEH. Consistent with the importance of hydrolase inhibition, sEH-null mice failed to vasodilate during hypoxia. CONCLUSION:: 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.

Original languageEnglish (US)
Pages (from-to)324-334
Number of pages11
JournalCirculation Research
Issue number3
StatePublished - Feb 4 2011


  • 15-deoxy prostaglandin J soluble epoxide hydrolase
  • hypoxia
  • redox signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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