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Pharmacologic Inhibition or Genetic Deletion of Soluble Epoxide Hydrolase Improves Survival Following Myocardial Infarction in Aged Mice
Author(s) -
Jamieson Lockhart,
Sosnowski Deanna K,
Darweshe Ahmed M,
Wang Wang,
Zhabyeyev Pavel,
Edin Matthew,
Zeldin Darryl,
Kassiri Zamaneh,
Oudit Gavin,
Seubert John M
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.817.8
Subject(s) - epoxide hydrolase 2 , arachidonic acid , metabolite , myocardial infarction , cardiac function curve , medicine , enzyme , endocrinology , mitochondrion , pharmacology , chemistry , biochemistry , heart failure
Objective Myocardial infarction (MI) accounts for a significant proportion of death and disability in aged individuals. CYP450 metabolism of n−6 PUFA arachidonic acid results in formation of numerous metabolites, called eicosanoids, that exhibit a wide range of cellular effects. Previous studies demonstrate eicosanoids can induce alterations to the mitochondria resulting in preserved cardiac function following ischemic injury. These metabolites are further metabolised by the enzyme soluble epoxide hydrolase (sEH) reducing their endogenous activity. This study investigated post‐ischemic cardiac function in aged mice with either genetic deletion or pharmacologic inhibition of sEH. Furthermore, a primary component of this study was to elucidate potential sex differences between male and female mice undergoing the experimental protocol. Methods Male and female WT and sEH null mice averaging 15 months old underwent permanent occlusion of the left anterior descending coronary artery (LAD). On the day of surgery, WT mice were given either vehicle (0.1% DMSO) or sEH inhibitor t AUCB (10 mg/ml dissolved in 0.1% DMSO) in drinking water for 28 days ad libitum . Cardiac function was assessed at baseline, 7 days and 28 days post‐MI by echocardiography and electrocardiogram. Protein expression was determined using immunoblotting techniques while mitochondrial enzymatic activities were assessed by spectrophotometry. Mitochondrial respiration in cardiac fibres was measured using a Clark‐type electrode. A full metabolite profile was determined in control and 28‐day post‐MI hearts by LCMS/MS. Results Pharmacological inhibition or genetic deletion of sEH was associated with fundamental changes in the n−3 and n−6 PUFA metabolite profile in cardiac tissue, correlating with better diastolic function, preserved mitochondrial respiration and overall improved survival at 28‐days post‐MI. Conclusions These data suggest that pharmacologic inhibition or genetic deletion of sEH elicits fundamental changes in the aged myocardium following long‐term ischemic injury. Support or Funding Information This research is supported by grants from the Canadian Heart and Stroke Foundation and Canadian Institute of Health Research. LJ is supported by a graduate studentship from Alberta Innovates‐Health Solutions. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .