Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice.
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-yl-ureido)-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.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
Clothilde
C
Roche
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
Marie
M
Besnier
INSERM U1060-CarMeN/INRA 1235/Université Claude Bernard Lyon 1, Oullins, France;
Roméo
R
Cassel
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
Najah
N
Harouki
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
David
D
Coquerel
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France; Department of Nephrology, Rouen University Hospital, Rouen, France;
Dominique
D
Guerrot
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
Lionel
L
Nicol
INSERM U1060-CarMeN/INRA 1235/Université Claude Bernard Lyon 1, Oullins, France;
Emmanuelle
E
Loizon
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
Isabelle
I
Remy-Jouet
Department of Entomology and Nematology, and UCD comprehensive Cancer Center, University of California, Davis, California; and.
Christophe
C
Morisseau
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
Paul
P
Mulder
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France;
Antoine
A
Ouvrard-Pascaud
INSERM U1060-CarMeN/INRA 1235/Université Claude Bernard Lyon 1, Oullins, France;
Anne-Marie
AM
Madec
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France; Department of Pharmacology, Rouen University Hospital, Rouen, France.
Vincent
V
Richard
Institut National de la Santé et de la Recherche Médicale (INSERM) U1096, Rouen, France; University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France; Department of Pharmacology, Rouen University Hospital, Rouen, France jeremy.Bellien@chu-rouen.fr.
Jeremy
J
Bellien
D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015777:Eicosanoids / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006331:Heart Diseases / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D001786:Blood Glucose; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D018836:Inflammation Mediators; D008055:Lipids; D014665:Vasodilator Agents; D009569:Nitric Oxide; D014508:Urea; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D005905:Glyburide
cardiac function; endothelium; insulin resistance; soluble epoxide hydrolase