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Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Significance The Mediterranean diet is characterized by consumption of unsaturated fats with vegetables rich in nitrite and nitrate, resulting in endogenous formation of nitro fatty acids. These reactive lipids adduct to soluble epoxide hydrolase, inhibiting it to lower blood pressure. Mice genetically engineered to be resistant to this adductive inhibition had high blood pressure basally and their hydrolase activity was fully resistant to inhibition by nitro fatty acid supplied directly or generated via the Mediterranean diet. Similarly nitro fatty acid lowered blood pressure and abrogated cardiac hypertrophy in a hypertension model in wild-type mice, but was ineffective in mutant mice. Thus, protection from hypertension afforded by the Mediterranean diet is mediated by nitro-fatty acid-dependent inhibition of soluble epoxide hydrolase. Soluble epoxide hydrolase (sEH) is inhibited by electrophilic lipids by their adduction to Cys521 proximal to its catalytic center. This inhibition prevents hydrolysis of the enzymes’ epoxyeicosatrienoic acid (EET) substrates, so they accumulate inducing vasodilation to lower blood pressure (BP). We generated a Cys521Ser sEH redox-dead knockin (KI) mouse model that was resistant to this mode of inhibition. The electrophilic lipid 10-nitro-oleic acid (NO2-OA) inhibited hydrolase activity and also lowered BP in an angiotensin II-induced hypertension model in wild-type (WT) but not KI mice. Furthermore, EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios were elevated in plasma from WT but not KI mice following NO2-OA treatment, consistent with the redox-dead mutant being resistant to inhibition by lipid electrophiles. sEH was inhibited in WT mice fed linoleic acid and nitrite, key constituents of the Mediterranean diet that elevates electrophilic nitro fatty acid levels, whereas KIs were unaffected. These observations reveal that lipid electrophiles such as NO2-OA mediate antihypertensive signaling actions by inhibiting sEH and suggest a mechanism accounting for protection from hypertension afforded by the Mediterranean diet.