Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase
| Autor: | Bruce D. Hammock, Alisa Kamynina, Philip Eaton, Jun Yang, Oleksandra Prysyazhna, Rebecca L. Charles, Bruce A. Freeman, Christophe Morisseau, Olena Rudyk |
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| Rok vydání: | 2014 |
| Předmět: |
Epoxide hydrolase 2
Linoleic acid Cardiomegaly Blood Pressure Mediterranean Diet Mediterranean Epoxyeicosatrienoic acid Inbred C57BL Cardiovascular chemistry.chemical_compound Mice Cellulase Animals Vasoconstrictor Agents 2.1 Biological and endogenous factors Sulfhydryl Compounds Gene Knock-In Techniques Nitrite Aetiology Nitrites Nutrition chemistry.chemical_classification Epoxide Hydrolases Multidisciplinary Nitrates Chemistry Animal Angiotensin II Prevention Fatty Acids Fatty acid thiol Biological Sciences Mice Mutant Strains Diet Mice Inbred C57BL Mutant Strains Vasodilation Disease Models Animal Enzyme Biochemistry Hypertension Disease Models cardiovascular system |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, vol 111, iss 22 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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