Improved endogenous epoxyeicosatrienoic acid production mends heart function via increased PGC 1α-mitochondrial functions in metabolic syndrome

Metabolic syndrome (MS) is a combination of symptoms characterized by central obesity, hypertension, hyperglycemia, and hyperlipidemia, which together increase the risk of heart disease, stroke and diabetes. In our study, we hypothesized that an EET-agonist (AUDA) would increase expression of PGC 1 alpha and improve mitochondrial and endothelial functions, resulting in improved heart function in a rat model of MS. To investigate this, rats were randomly divided into four groups: 1) Control; 2) MS thorn ABCT; 3) MS thorn AUDA; and 4) MS thorn AUDA thorn SnMP. MS rats were fed a high-fructose diet for 16 weeks and developed elevated inflammatory mediators, oxidative stress, and significant decreases in fractional shortening and hemodynamic parameters, indicating cardiac dysfunction. Histology revealed myocardial fibrosis and myocyte hypertrophy. AUDA improves mitochondrial function proven by increase in mt copy number and ATP production and significantly increased expression of PGC-1 alpha and HO-1 in the rats and normalization of inflammatory cytokines, oxidative stress, and improves in cardiac function and myocardial fibrosis. These benefits were reversed by SnMP. Furthermore, AUDA increases eNOS but decreases iNOS expression which improved endothelial function. We therefore demonstrate that endogenous EET upregulation plays a novel role in protecting the heart from MS by regulating mitochondrial and endothelial function. (c) 2018 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.