0211 Prevention of cardiovascular, renal and metabolic abnormalities by soluble epoxide hydrolase inhibition in a murine model of type 2 diabetes

ObjectiveEpoxyeicosatrienoic acids (EETs) are synthesized from arachidonic acid, notably in endothelial cells, and display attractive metabolic, vasodilatory and anti-inflammatory properties. We demonstrated previously that inhibiting EET degradation mediated by soluble epoxide hydrolase (sEH) reduces hypertension and heart failure, and others reported that it improves glucose homeostasis in type 2 diabetes. However, the impact of such strategy on target organ damage in diabetes remains to be clarified.Materials and methodsThe pharmacological sEH inhibitor t-AUCB (10 mg/l in drinking water) was administered for 8 weeks in mice subjected to a high-fat diet (HFD, 60% fat) for 16 weeks. Mice on control chow diet (10% fat), non-treated HFD mice and HFD mice treated with glibenclamide (80 mg/l) served as controls.ResultsGlibenclamide and t-AUCB similarly prevented the increased fasting glycemia in HFD mice (Control: 5.4±0.2; HFD: 8.0±0.8; HFD+GLI: 5.1±0.3; HFD+t-AUCB: 5.6±0.2mmol/L; p<0.05). However, only t-AUCB improved glucose tolerance and decreased gluconeogenesis. In parallel, t-AUCB prevented adipose tissue activation and dyslipidemia. Moreover, t-AUCB improved coronary endothelial function and prevented diastolic dysfunction, as shown by echocardiography (E/A ratio; Control: 1.25±0.02; HFD: 1.05±0.03; HFD+GLI: 1.07±0.04; HFD+t-AUCB: 1.23±0.04; p<0.05) and invasive hemodynamics (LVEDPVR; Control: 1.9±0.55; HFD: 3.8±0.61; HFD+GLI: 3.1±0.8; HFD+t- AUCB: 1.88±0.2mmHg/RVU; p