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Redox regulation of soluble epoxide hydrolase by 15-deoxy-Δ-prostaglandin J2 controls coronary hypoxic vasodilation

Item Type:Article
Title:Redox regulation of soluble epoxide hydrolase by 15-deoxy-Δ-prostaglandin J2 controls coronary hypoxic vasodilation
Creators Name:Charles, R.L. and Burgoyne, J.R. and Mayr, M. and Weldon, S.M. and Hubner, N. and Dong, H. and Morisseau, C. and Hammock, B.D. and Landar, A.L. and Eaton, P.
Abstract:Rationale: 15-Deoxy-{delta}-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. Methods and 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.
Keywords:15-Deoxy Prostaglandin J2, Soluble Epoxide Hydrolase, Redox Signaling, Hypoxia, Animals, Mice, Rats, Wistar Rats
Source:Circulation Research
ISSN:0009-7330
Publisher:American Heart Association (U.S.A.)
Volume:108
Number:3
Page Range:324-334
Date:4 February 2011
Official Publication:https://doi.org/10.1161/CIRCRESAHA.110.235879
PubMed:View item in PubMed

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