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

Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):8167-72. doi: 10.1073/pnas.1402965111. Epub 2014 May 19.


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.

Keywords: cardiovascular; thiol.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Blood Pressure
  • Cardiomegaly / diet therapy
  • Cardiomegaly / prevention & control
  • Cellulase
  • Diet, Mediterranean*
  • Disease Models, Animal
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / metabolism*
  • Fatty Acids / metabolism*
  • Gene Knock-In Techniques
  • Hypertension / chemically induced
  • Hypertension / diet therapy*
  • Hypertension / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nitrates / metabolism
  • Nitrites / metabolism
  • Sulfhydryl Compounds / metabolism
  • Vasoconstrictor Agents / pharmacology
  • Vasodilation / drug effects
  • Vasodilation / physiology


  • Fatty Acids
  • Nitrates
  • Nitrites
  • Sulfhydryl Compounds
  • Vasoconstrictor Agents
  • Angiotensin II
  • solubilase
  • Cellulase
  • Epoxide Hydrolases
  • Ephx2 protein, mouse