Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice

Clothilde Roche, Marie Besnier, Roméo Cassel, Najah Harouki, David Coquerel, Dominique Guerrot, Lionel Nicol, Emmanuelle Loizon, Isabelle Remy-Jouet, Christophe Morisseau, Paul Mulder, Antoine Ouvrard-Pascaud, Anne Marie Madec, Vincent Richard, Jeremy Bellien

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-ylureido)- cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors L-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice.

Original languageEnglish (US)
Pages (from-to)H1020-H1029
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume308
Issue number9
DOIs
StatePublished - 2015

Fingerprint

Epoxide Hydrolases
Insulin
Glyburide
Myography
Fats
Inflammation
Glucose
Acids
Gluconeogenesis
Cardiomegaly
High Fat Diet
Nonesterified Fatty Acids
Nitric Oxide Synthase
Drinking Water
LDL Cholesterol
Acetylcholine
Weight Gain
Endothelium
Echocardiography
Insulin Resistance

Keywords

  • Cardiac function
  • Endothelium
  • Insulin resistance
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice. / Roche, Clothilde; Besnier, Marie; Cassel, Roméo; Harouki, Najah; Coquerel, David; Guerrot, Dominique; Nicol, Lionel; Loizon, Emmanuelle; Remy-Jouet, Isabelle; Morisseau, Christophe; Mulder, Paul; Ouvrard-Pascaud, Antoine; Madec, Anne Marie; Richard, Vincent; Bellien, Jeremy.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 308, No. 9, 2015, p. H1020-H1029.

Research output: Contribution to journalArticle

Roche, C, Besnier, M, Cassel, R, Harouki, N, Coquerel, D, Guerrot, D, Nicol, L, Loizon, E, Remy-Jouet, I, Morisseau, C, Mulder, P, Ouvrard-Pascaud, A, Madec, AM, Richard, V & Bellien, J 2015, 'Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice', American Journal of Physiology - Heart and Circulatory Physiology, vol. 308, no. 9, pp. H1020-H1029. https://doi.org/10.1152/ajpheart.00465.2014
Roche, Clothilde ; Besnier, Marie ; Cassel, Roméo ; Harouki, Najah ; Coquerel, David ; Guerrot, Dominique ; Nicol, Lionel ; Loizon, Emmanuelle ; Remy-Jouet, Isabelle ; Morisseau, Christophe ; Mulder, Paul ; Ouvrard-Pascaud, Antoine ; Madec, Anne Marie ; Richard, Vincent ; Bellien, Jeremy. / Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice. In: American Journal of Physiology - Heart and Circulatory Physiology. 2015 ; Vol. 308, No. 9. pp. H1020-H1029.
@article{cdf066756b754318a09bd99545f3eb9f,
title = "Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice",
abstract = "This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-ylureido)- cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60{\%} fat) for 16 wk. Mice on control chow diet (10{\%} fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors L-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice.",
keywords = "Cardiac function, Endothelium, Insulin resistance, Soluble epoxide hydrolase",
author = "Clothilde Roche and Marie Besnier and Rom{\'e}o Cassel and Najah Harouki and David Coquerel and Dominique Guerrot and Lionel Nicol and Emmanuelle Loizon and Isabelle Remy-Jouet and Christophe Morisseau and Paul Mulder and Antoine Ouvrard-Pascaud and Madec, {Anne Marie} and Vincent Richard and Jeremy Bellien",
year = "2015",
doi = "10.1152/ajpheart.00465.2014",
language = "English (US)",
volume = "308",
pages = "H1020--H1029",
journal = "American Journal of Physiology - Renal Fluid and Electrolyte Physiology",
issn = "1931-857X",
publisher = "American Physiological Society",
number = "9",

}

TY - JOUR

T1 - Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice

AU - Roche, Clothilde

AU - Besnier, Marie

AU - Cassel, Roméo

AU - Harouki, Najah

AU - Coquerel, David

AU - Guerrot, Dominique

AU - Nicol, Lionel

AU - Loizon, Emmanuelle

AU - Remy-Jouet, Isabelle

AU - Morisseau, Christophe

AU - Mulder, Paul

AU - Ouvrard-Pascaud, Antoine

AU - Madec, Anne Marie

AU - Richard, Vincent

AU - Bellien, Jeremy

PY - 2015

Y1 - 2015

N2 - This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-ylureido)- cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors L-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice.

AB - This study addressed the hypothesis that inhibiting the soluble epoxide hydrolase (sEH)-mediated degradation of epoxy-fatty acids, notably epoxyeicosatrienoic acids, has an additional impact against cardiovascular damage in insulin resistance, beyond its previously demonstrated beneficial effect on glucose homeostasis. The cardiovascular and metabolic effects of the sEH inhibitor trans-4-[4-(3-adamantan-1-ylureido)- cyclohexyloxy]-benzoic acid (t-AUCB; 10 mg/l in drinking water) were compared with those of the sulfonylurea glibenclamide (80 mg/l), both administered for 8 wk in FVB mice subjected to a high-fat diet (HFD; 60% fat) for 16 wk. Mice on control chow diet (10% fat) and nontreated HFD mice served as controls. Glibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice, but only t-AUCB improved glucose tolerance and decreased gluconeogenesis, without modifying weight gain. Moreover, t-AUCB reduced adipose tissue inflammation, plasma free fatty acids, and LDL cholesterol and prevented hepatic steatosis. Furthermore, only the sEH inhibitor improved endothelium-dependent relaxations to acetylcholine, assessed by myography in isolated coronary arteries. This improvement was related to a restoration of epoxyeicosatrienoic acid and nitric oxide pathways, as shown by the increased inhibitory effects of the nitric oxide synthase and cytochrome P-450 epoxygenase inhibitors L-NA and MSPPOH on these relaxations. Moreover, t-AUCB decreased cardiac hypertrophy, fibrosis, and inflammation and improved diastolic function, as demonstrated by the increased E/A ratio (echocardiography) and decreased slope of the end-diastolic pressure-volume relation (invasive hemodynamics). These results demonstrate that sEH inhibition improves coronary endothelial function and prevents cardiac remodeling and diastolic dysfunction in obese insulin-resistant mice.

KW - Cardiac function

KW - Endothelium

KW - Insulin resistance

KW - Soluble epoxide hydrolase

UR - http://www.scopus.com/inward/record.url?scp=84929698431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929698431&partnerID=8YFLogxK

U2 - 10.1152/ajpheart.00465.2014

DO - 10.1152/ajpheart.00465.2014

M3 - Article

C2 - 25724490

AN - SCOPUS:84929698431

VL - 308

SP - H1020-H1029

JO - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

JF - American Journal of Physiology - Renal Fluid and Electrolyte Physiology

SN - 1931-857X

IS - 9

ER -