Cited by 64Eicosanoids and Hypertension PharmacologyCardiovascular Function and Risk FactorsCardiac Fibrosis and Remodeling

Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure

Merabet, Nassiba, Bellien, Jeremy, Glevarec, Etienne, Nicol, Lionel, Lucas, Daniele, Remy-Jouet, Isabelle, Bounoure, Frederic, Dreano, Yvonne +3 more·2012·Journal of Molecular and Cellular Cardiology

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.

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Crossref · 10.1016/j.yjmcc.2011.11.015

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  • Various signs of increased oxidative stress have been reported in heart failure, ventricular hypertrophy, myocardial infarction, diabetes, and other conditions.

    “Various signs of increased oxidative stress have been reported in various cardiovascular-related diagnoses such as heart failure (Dai et al. 2012), ventricular hypertrophy (Dai et al. 2011), myocardial infarction (Merabet et al. 2012), diabetes (Anderson et al. 2009) and other conditions.”

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Authors
Merabet, N., Bellien, J., Glevarec, E., Nicol, L., Lucas, D., Remy-Jouet, I., Bounoure, F., Dreano, Y., Wecker, D., Thuillez, C., & Mulder, P.
Affiliations
Inserm (FR)
Venue
Journal of Molecular and Cellular Cardiology
Publisher
Elsevier BV
Published
2012-03
Volume
52
Issue
3
Pages
660-666
ISSN
0022-2828 (ISSN-L)
OpenAlex
W1977307022
Cited by
63
References
38
Citations by year
2025: 1 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 7 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 6 · 2016: 5 · 2015: 7 · 2014: 6 · 2013: 6 · 2012: 5
FWCI
2.30
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Molecular and Cellular Cardiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
auDA Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
soluble epoxide hydrolase inhibition, epoxyeicosatrienoic acids, chronic heart failure, myocardial perfusion, left ventricular function, left ventricular remodeling, AUDA, cytochrome P450 epoxygenase, reactive oxygen species, oxidative stress, hypoxia-inducible factor-1α, peripheral vasodilation, cardiac output, collagen density
MeSH terms
Adamantane, Animals, Coronary Circulation, Disease Models, Animal, Enzyme Inhibitors, Epoxide Hydrolases, Heart Failure, Hemodynamics, Lauric Acids, Male, Myocardial Infarction, Myocardium, Nitric Oxide, Signal Transduction, Ventricular Function, Left, Rats, Wistar, Oxidative Stress, Phosphatidylinositol 3-Kinases, Ventricular Remodeling, Proto-Oncogene Proteins c-akt, Rats

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