title: Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure.
abstract: The study addressed the hypothesis that soluble epoxide hydrolase (sEH) inhibition, which increases cardiovascular protective epoxyeicosatrienoic acids (EETs), exerts beneficial effects in an established chronic heart failure (CHF) model. In CHF rats, left ventricular (LV) function, perfusion and remodeling were assessed using MRI and invasive hemodynamics after 42-day (starting 8 days after coronary ligation) and delayed 3-day (starting 47 days after coronary ligation) treatments with the sEH inhibitor AUDA (twice 0.25 mg/day). Delayed 3-day and 42-day AUDA increased plasma EETs demonstrating the effective inhibition of sEH. Delayed 3-day and 42-day AUDA enhanced cardiac output without change in arterial pressure, thus reducing total peripheral resistance. Both treatment periods increased the slope of the LV end-systolic pressure-volume relation, but only 42-day AUDA decreased LV end-diastolic pressure, relaxation constant Tau and the slope of the LV end-diastolic pressure-volume relation, associated with a reduced LV diastolic volume and collagen density. Delayed 3-day and, to a larger extent, 42-day AUDA increased LV perfusion associated with a decreased LV hypoxia-inducible factor-1alpha. Both treatment periods decreased reactive oxygen species level and increased reduced-oxidized glutathione ratio. Finally, MSPPOH, an inhibitor of the EET-synthesizing enzyme cytochrome epoxygenases, abolished the beneficial effects of 3-day AUDA on LV function and perfusion. Augmentation of EET availability by pharmacological inhibition of sEH increases LV diastolic and systolic functions in established CHF. This notably results from short-term processes, i.e. increased LV perfusion, reduced LV oxidative stress and peripheral vasodilatation, but also from long-term effects, i.e. reduced LV remodeling.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U644, University of Rouen, Rouen, France.
authors.forename: Nassiba
authors.initials: N
authors.lastname: Merabet
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bellien
authors.forename: Etienne
authors.initials: E
authors.lastname: Glevarec
authors.forename: Lionel
authors.initials: L
authors.lastname: Nicol
authors.forename: Daniele
authors.initials: D
authors.lastname: Lucas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Remy-Jouet
authors.forename: Frederic
authors.initials: F
authors.lastname: Bounoure
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dreano
authors.forename: Didier
authors.initials: D
authors.lastname: Wecker
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007850:Lauric Acids / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D004791:Enzyme Inhibitors; D007850:Lauric Acids; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D004851:Epoxide Hydrolases; D000218:Adamantane