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-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.

• Authors: 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
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 308 Issue 9 Pg. H1020-9 (May 01 2015) ISSN: 1522-1539 [Electronic] United States
• PMID: 25724490 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid
• Benzoates
• Blood Glucose
• Eicosanoids
• Enzyme Inhibitors
• Hypoglycemic Agents
• Inflammation Mediators
• Lipids
• Vasodilator Agents
• Nitric Oxide
• Urea
• Epoxide Hydrolases
• Ephx2 protein, mouse
• Glyburide

Topics

• Animals
• Benzoates (pharmacology)
• Blood Glucose (drug effects, metabolism)
• Coronary Vessels (drug effects, enzymology, physiopathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Eicosanoids (metabolism)
• Endothelium, Vascular (drug effects, enzymology, physiopathology)
• Enzyme Inhibitors (pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors, metabolism)
• Glyburide (pharmacology)
• Heart Diseases (enzymology, etiology, physiopathology, prevention & control)
• Hypoglycemic Agents (pharmacology)
• Inflammation Mediators (metabolism)
• Insulin Resistance
• Lipids (blood)
• Male
• Mice
• Nitric Oxide (metabolism)
• Obesity (blood, complications, drug therapy, enzymology, physiopathology)
• Time Factors
• Urea (analogs & derivatives, pharmacology)
• Vasodilation (drug effects)
• Vasodilator Agents (pharmacology)
• Ventricular Function, Left (drug effects)
• Ventricular Remodeling (drug effects)