title: Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: Insight gained using metabolomic approaches.
abstract: Myocardial infarction (MI) leading to myocardial cell loss represents one of the common causes leading to cardiac failure. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase (sEH) inhibitors in cardiac hypertrophy. sEH catalizes the conversion of epoxyeicosatrienoic acids (EETs) to form the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are products of cytochrome P450 epoxygenases that have vasodilatory properties. Additionally, EETs inhibit the activation of nuclear factor (NF)-kappaB-mediated gene transcription. Motivated by the potential to uncover a new class of therapeutic agents for cardiovascular diseases which can be effectively used in clinical setting, we directly tested the biological effects of sEH inhibitors (sEHIs) on the progression of cardiac remodeling using a clinically relevant murine model of MI. We demonstrated that sEHIs were highly effective in the prevention of progressive cardiac remodeling post MI. Using metabolomic profiling of the inflammatory lipid mediators, we documented a significant decrease in EETs/DHETs ratio in MI model predicting a heightened inflammatory state. Treatment with sEHIs resulted in a change in the pattern of lipid mediators from one of inflammation towards resolution. Moreover, the oxylipin profiling showed a striking parallel to the changes in inflammatory cytokines in this model. Our study provides evidence for a possible new therapeutic strategy to improve cardiac function post MI.
authors.affiliation: Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.forename: Valeriy
authors.initials: V
authors.lastname: Timofeyev
authors.forename: Hong
authors.initials: H
authors.lastname: Qiu
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Dipika
authors.initials: D
authors.lastname: Tuteja
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Hideki
authors.initials: H
authors.lastname: Mochida
authors.forename: Reginald
authors.initials: R
authors.lastname: Low
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000097:blood / Q000150:complications / Q000517:prevention & control; D001565:Benzoates / Q000494:pharmacology*; D002853:Chromatography, Liquid; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D006334:Heart Function Tests; D020287:In Situ Nick-End Labeling; D018836:Inflammation Mediators / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D055432:Metabolomics; D051379:Mice; D009203:Myocardial Infarction / Q000150:complications / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D012995:Solubility; D053719:Tandem Mass Spectrometry; D014463:Ultrasonography; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D016207:Cytokines; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D014508:Urea; D004851:Epoxide Hydrolases