The contribution of chymase-dependent formation of AngII to cardiac dysfunction in metabolic syndrome of young rats: roles of fructose and EETs.

The roles of ACE-independent AngII production via chymase and therapeutic potential of epoxyeicosatrienoic acids (EETs) in fructose-induced metabolic syndrome (MetS) in the adolescent population remain elusive. Thus, we tested the hypothesis that high fructose diet (HFD) in young rats elicits chymase-dependent increases in AngII production and oxidative stress, responses that are reversible by TPPU, an inhibitor of soluble epoxide hydrolase (sEH) that metabolizes EETs. Three groups of weanling rats (21-day-old) were fed a normal diet, 60% HFD and HFD with TPPU respectively, for 30 days. HFD rats developed MetS, characterized by hyperglycemia, hyperinsulinemia and hypertension, and associated with decreases in cardiac output and stroke volume, and loss of NO-modulation of myocardial oxygen consumption; all impairments were normalized by TPPU that significantly elevated circulating 11,12-EET, a major cardiac EET isoform. In the presence of comparable cardiac ACE expression/activity among the three groups, HFD rats exhibited significantly greater chymase-dependent AngII formation in hearts, as indicated by an augmented cardiac chymase content as a function of enhanced mast cell degranulation. The enhanced chymase-dependent AngII production was paralleled with increases in AngII type 1 receptor (AT1R) expression and NADPH oxidase (Nox)-induced superoxide, alterations that were significantly reversed by TPPU. Conversely, HFD-induced downregulation of cardiac ACE2, followed by lower Ang1-7 level displayed in an TPPU-irreversible manner. In conclusions, HFD-driven adverse chymase/AngII/AT1R/Nox/superoxide signaling in young rats was prevented by inhibition of sEH via at least in part, an EET-mediated stabilization of mast cells, highlighting chymase and sEH as therapeutic targets during treatment of MetS.