title: Inhibition of Soluble Epoxide Hydrolase Limits Mitochondrial Damage and Preserves Function Following Ischemic Injury.
abstract: OBJECTIVE
  Myocardial ischemia can result in marked mitochondrial damage leading to cardiac dysfunction, as such identifying novel mechanisms to limit mitochondrial injury is important. This study investigated the hypothesis that inhibiting soluble epoxide hydrolase (sEH), responsible for converting epoxyeicosatrienoic acids to dihydroxyeicosatrienoic acids protects mitochondrial from injury caused by myocardial infarction.
  
  
  METHODS
  sEH null and WT littermate mice were subjected to surgical occlusion of the left anterior descending (LAD) artery or sham operation. A parallel group of WT mice received an sEH inhibitor, trans-4-[4-(3-adamantan-1-y1-ureido)-cyclohexyloxy]-benzoic acid (tAUCB; 10 mg/L) or vehicle in the drinking water 4 days prior and 7 days post-MI. Cardiac function was assessed by echocardiography prior- and 7-days post-surgery. Heart tissues were dissected into infarct, peri-, and non-infarct regions to assess ultrastructure by electron microscopy. Complexes I, II, IV, citrate synthase, PI3K activities, and mitochondrial respiration were assessed in non-infarct regions. Isolated working hearts were used to measure the rates of glucose and palmitate oxidation.
  
  
  RESULTS
  Echocardiography revealed that tAUCB treatment or sEH deficiency significantly improved systolic and diastolic function post-MI compared to controls. Reduced infarct expansion and less adverse cardiac remodeling were observed in tAUCB-treated and sEH null groups. EM data demonstrated mitochondrial ultrastructure damage occurred in infarct and peri-infarct regions but not in non-infarct regions. Inhibition of sEH resulted in significant improvements in mitochondrial respiration, ATP content, mitochondrial enzymatic activities and restored insulin sensitivity and PI3K activity.
  
  
  CONCLUSIONS
  Inhibition or genetic deletion of sEH protects against long-term ischemia by preserving cardiac function and maintaining mitochondrial efficiency.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, 2-020M Katz Group Centre for Pharmacy and Health Research, University of Alberta Edmonton, AB, Canada.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Akhnokh
authors.affiliation: Guangdong Laboratory Animal Monitoring Institute Guangdong, China.
authors.forename: Feng Hua
authors.initials: FH
authors.lastname: Yang
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, 2-020M Katz Group Centre for Pharmacy and Health Research, University of Alberta Edmonton, AB, Canada.
authors.forename: Victor
authors.initials: V
authors.lastname: Samokhvalov
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, 2-020M Katz Group Centre for Pharmacy and Health Research, University of Alberta Edmonton, AB, Canada.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Jamieson
authors.affiliation: Imaging Core Facility, Faculty of Medicine and Dentistry, University of Alberta Edmonton, AB, Canada.
authors.forename: Woo Jung
authors.initials: WJ
authors.lastname: Cho
authors.affiliation: Mazankowski Alberta Heart Institute, University of AlbertaEdmonton, AB, Canada; Department of Pharmacology, Faculty of Medicine and Dentistry, University of AlbertaEdmonton, AB, Canada.
authors.forename: Cory
authors.initials: C
authors.lastname: Wagg
authors.affiliation: Mazankowski Alberta Heart Institute, University of AlbertaEdmonton, AB, Canada; Department of Physiology, Faculty of Medicine and Dentistry, University of AlbertaEdmonton, AB, Canada.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Takawale
authors.affiliation: Mazankowski Alberta Heart Institute, University of AlbertaEdmonton, AB, Canada; Department of Physiology, Faculty of Medicine and Dentistry, University of AlbertaEdmonton, AB, Canada.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: Mazankowski Alberta Heart Institute, University of AlbertaEdmonton, AB, Canada; Department of Pharmacology, Faculty of Medicine and Dentistry, University of AlbertaEdmonton, AB, Canada; Department of Pediatrics, Faculty of Medicine and Dentistry, University of AlbertaEdmonton, AB, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.affiliation: Department of Entomology and Nematology Comprehensive Cancer Center, University of California, Davis Davis, CA, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Mazankowski Alberta Heart Institute, University of AlbertaEdmonton, AB, Canada; Department of Physiology, Faculty of Medicine and Dentistry, University of AlbertaEdmonton, AB, Canada.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Kassiri
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, 2-020M Katz Group Centre for Pharmacy and Health Research, University of AlbertaEdmonton, AB, Canada; Mazankowski Alberta Heart Institute, University of AlbertaEdmonton, AB, Canada; Department of Pharmacology, Faculty of Medicine and Dentistry, University of AlbertaEdmonton, AB, Canada.
authors.forename: John M
authors.initials: JM
authors.lastname: Seubert
keywords: acute myocardial infarction; arachidonic acid; mitochondrial efficiency; soluble epoxide hydrolase