Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid 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.
King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom;
Rebecca L
RL
Charles
King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom;
Olena
O
Rudyk
King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom;
Oleksandra
O
Prysyazhna
King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom;
Alisa
A
Kamynina
Department of Entomology and Nematology, andUniversity of California, Davis Comprehensive Cancer Center, University of California, Davis, CA 95616; and.
Jun
J
Yang
Department of Entomology and Nematology, andUniversity of California, Davis Comprehensive Cancer Center, University of California, Davis, CA 95616; and.
Christophe
C
Morisseau
Department of Entomology and Nematology, andUniversity of California, Davis Comprehensive Cancer Center, University of California, Davis, CA 95616; and.
Bruce D
BD
Hammock
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
Bruce A
BA
Freeman
King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, The Rayne Institute, St. Thomas' Hospital, London SE1 7EH, United Kingdom; philip.eaton@kcl.ac.uk.
Philip
P
Eaton
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000178:diet therapy / Q000517:prevention & control; D002480:Cellulase; D038441:Diet, Mediterranean; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006973:Hypertension / Q000139:chemically induced / Q000178:diet therapy* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D005227:Fatty Acids; D009566:Nitrates; D009573:Nitrites; D013438:Sulfhydryl Compounds; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C430283:solubilase; D002480:Cellulase; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse
cardiovascular; thiol