Inhibition of sEH prevents high fructose‐induced impairement of myocardial oxygen comsumption in young rats

Abstract

High fructose diet increases tissue oxidative stress and has been shown to be detrimental to cardiac function. Epoxyeicosainoic acids (EETs) are metabolites of arachidonic acid, which possess cardioprotective properties and are metabolized by soluble epoxide hydrolase (sEH). Therefore, inhibition of sEH is proven to be beneficial to cardiovascular function. The specific impact of a high fructose diet and the role of EETs/sEH in the regulation of cardiac function in the adolescent population have not been studied. To test the hypothesis that sEH inhibition attenuates the adverse action of fructose consumption on the heart of young rats, 4 week old rats were fed a normal diet (as control; ND) or a high fructose diet (HFD) for 30 days, without or with concomitant administration of TPPU, a specific sEH inhibitor, by oral‐gavage (1mg/kg body weight: HFD‐TPPU).MethodsCardiac output was analyzed by echocardiography and blood pressure was recorded using tail‐cuff measurements. Myocardial oxygen consumption (MV̇o2) was measured in freshly isolated left ventricular tissue from all groups of rats under control conditions and following incubation of tissue with the nitric oxide (NO) synthase inhibitor Nω‐nitro‐l‐arginine methyl ester (L‐NAME; 10−4M), or NADPH oxidase inhibitor (Nox), apocynin (10−4M) for 1 hour. Cytosolic and mitochondrial superoxide levels were determined by HPLC‐fluorescence detection via incubation of myocardial tissues with dihydroethidium (DHE) or Mitosox. Nox 2 expression was measured via western blot analysis.ResultsFructose feeding significantly impaired MV̇o2 compared to hearts of ND rats, as indicated by the loss of NO‐mediated regulation of MV̇o2. Incubation of myocardial tissue isolated from the ND group with L‐NAME yielded the same pattern as fructose feeding, further confirming that the NO‐mediated response is compromised with high fructose consumption. The treatment of HFD rats with TPPU normalized their MV̇o2 to the level of ND rats. Furthermore, incubation of myocardial tissues isolated from HFD rats with apocynin elicited normalized MV̇o2, comparable to that observed in HFD‐TPPU rats. In addition, mitochondrial superoxide and Nox 2 expression were significantly increased in myocardial tissue of HFD rats compared to ND and HFD‐TPPU rats. Thus, we conclude that 1) high fructose‐induced increase in oxidative stress is responsible for impaired NO‐mediated regulation of MV̇o2. 2) Inhibition of sEH reversed the oxidative stress‐induced impairment of MV̇o2 via perhaps, increases in tissue levels of antioxidant EETs.Support or Funding InformationThis work was supported by HL070653 and HL129797This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.