An Omega-3 Epoxide of Docosahexaenoic Acid Lowers Blood Pressure in Angiotensin-II–Dependent Hypertension

Abstract

Mediators of anti-hypertensive actions of docosahexaenoic acid (DHA) are largely unknown. The omega-3 epoxide of DHA, 19, 20-EDP (epoxydocosapentaenoic acid) is metabolized by soluble epoxide hydrolase (sEH), which also metabolizes the anti-inflammatory and anti-hypertensive arachidonic acid (ARA) epoxides, EETs (epoxyeicosatrienoic acids). Based in part on plasma levels of EDPs following a DHA-rich diet, we hypothesized that 19, 20-EDP contributes to the anti-hypertensive actions of DHA in angiotensin-II dependent hypertension. Treatment individually with 19, 20-EDP, and a potent sEH inhibitor (sEHI) TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea) significantly lowered blood pressure (BP) as compared to angiotensin-II infused animals. The largest reduction in BP was obtained with the combination of 19, 20-EDP and TPPU, which was more efficacious than the combination of 14, 15-EET and TPPU. Oxylipin profiling revealed that 19, 20-EDP and 14, 15-EET infusion affected mostly metabolites of the P450 pathway but also renal levels of prostaglandin-E2. Our findings suggest that 19, 20- EDP is a mediator of the anti-hypertensive effects of DHA in angiotensin-II dependent hypertension. It appears that 19, 20- EDP requires metabolic stabilization with a sEHI to be most effective in lowering BP, although both TPPU and 19, 20- EDP are so effective on their own that demonstrating additive or synergistic interactions is difficult.

Inhibition of soluble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: Role for omega-3 epoxides

“…In our study, we used fat-1 mice as an optimal model of omega-3 enrichment, in which the stabilization of CYP-derived epoxides by a sEH inhibitor reinforced the omega-3-dependent reduction in hepatic inflammation and intrahepatic lipid deposition. Taken together, our findings expand to the metabolic field the initial observation that an omega-3-rich diet in combination with a sEH inhibitor exerts antihypertensive actions (6).…”

“…In addition to omega-6s, CYP epoxygenases also convert the omega-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into novel epoxyeicosatetraenoic (EEQs) and epoxydocosapentaenoic (EDPs) acids, respectively (4,5). These omega-3-derived epoxides also exert salutary actions and are even more effective and potent than omega-6-derived EETs (4)(5)(6)(7)(8).…”

“…sEH is a cytosolic enzyme with epoxide hydrolase and lipid phosphatase activities that catalyzes the rapid hydrolysis of EETs, EEQs and EDPs by adding water to these EpFA and converting them into inactive or less active 1,2-diols (10). Accordingly, inhibition of sEH exerts beneficial actions in controlling vascular tone, inflammation, and pain, and this strategy has shown its therapeutic potential for long-term use in hypertension, diabetes, renal disease, organ damage, and vascular remodeling (6,(9)(10)(11)(12).…”

The 2014 Bernard B. Brodie Award Lecture—Epoxide Hydrolases: Drug Metabolism to Therapeutics for Chronic Pain

“…Several of the effects seen with EETs have been observed with the epoxide derivatives of v-3 fatty acids, including epoxyeicosatetraenoic acid, an epoxide of eicosapentaenoic acid, and epoxydocosapentaenoic acid (EpDPE), an epoxide of docosahexaenoic acid Ulu et al, 2014). In the case of angiotensin II (AngII)-induced hypertension, the connection between an increase in EpDPEs caused by dietary v-3 fatty acid consumption and sEH inhibitor treatment has been clearly demonstrated.…”

“…By contrast, EETs with sEH inhibitors were not as potent toward reducing blood pressure. Data are replotted from Ulu et al (2014). (C) In a rat model of streptozocin-induced diabetic neuropathy, an v-3-rich diet had minimal effect at increasing pain thresholds relative to those on an oleic oil-based diet.…”