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

Charles, Rebecca L.; Rudyk, Olena; Prysyazhna, Oleksandra; Kamynina, Alisa; Yang, Jun; Morisseau, Christophe; Hammock, Bruce D.; Freeman, Bruce Α.; Eaton, Philip

doi:10.1073/pnas.1402965111

Cited by 85 publications

(86 citation statements)

References 52 publications

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“…Although no such evidence has been published, this speculation is consistent with increased vasodilator tone in normotensive or hypertensive experimental models when production of vascular EETs is enhanced by dietary means 15 or by administration of EET analogs. 16 These observations likely reflect EET attenuation of vascular myogenic responses in resistance arterioles, as shown in sEH knockout mice or with sEH inhibitors.…”

Section: Discussionmentioning

confidence: 52%

Two Pools of Epoxyeicosatrienoic Acids in Humans

Elijovich

Milne

Brown³

et al. 2018

Hypertension

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E poxyeicosatrienoic acids (EETs) are products of epoxygenation of arachidonic acid. They participate in cardiovascular regulation via vasodilator and natriuretic effects. Research on their actions used urine or plasma measurements of their 4 active regioisomers (5,8,11,and 14, and their relatively inactive derivatives, the dihydroxyeicosatrienoic acids [DHETs]. The latter are produced by enzymatic (soluble epoxide hydrolase [sEH]) or nonenzymatic (eg, pH, oxidative stress) degradation.Previous studies in animals suggested that urine and plasma EETs may reflect 2 distinct pools with different functions. The volume of distribution of intravenous radiolabeled 14,15-EET in dogs approximates their plasma volume, and no radioactivity can be detected in their urine.1 Plasma EET responses to regulatory PPARα (peroxisome proliferatoractivated receptor α) ligands in mice run parallel to Cyp2c epoxygenase expression and EET biosynthesis in the liver. These studies suggest that plasma EETs reflect a systemic, not a renal pool. Conversely, increased renal EET content produced by dopamine agonists in mice is not associated with changes in plasma EETs,3 indicating that the renal EET pool might be better reflected by urine measurements. Our first aim was to assess whether these putative pools could be uncovered by studying clinical and biochemical correlates of urine and plasma EETs in normal volunteers; that is, normotensive, saltresistant (SR) subjects, during salt loading and depletion.EETs may play a role in salt sensitivity of blood pressure (BP). Salt stimulates renal microsomal biosynthesis of EETs in normal Sprague Dawley 4 and Dahl-R rats, 5 whereas this response is absent in the salt-sensitive (SS) Dahl-S strain, leading to hypertension with reduced renal expression of the epoxygenase CYP2C23 and urine excretion of EETs. 5 In SR rats, the epoxygenase inhibitor clotrimazole decreases urinary EETs and reproduces SS hypertension.5 Cyp4a10 knockout mice, which have reduced renal epoxygenase (Cyp2c44) activity, 6 and the Cyp2c44 knockout, 7 have diminished urine EETs and amiloride-sensitive hypertension. This is associated with decreased inactivating threonine phosphorylation of γENaC (epithelial sodium channel), 7 which is reversible by the PPARα ligands that stimulate epoxygenases.6 Our second aim was to investigate whether SS subjects exhibit differences in urine or plasma EETs levels or in their responses to changes in salt balance or in their clinical or biochemical correlates compared with SR. To avoid confounding effects of established hypertension, we performed these studies in normotensive volunteers.Abstract-We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na + /24 hours, HiNa) and depletion (10 mEq Na + /24 hours+furosemide 40 mg×3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrie...

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Section: Discussionmentioning

confidence: 52%

Two Pools of Epoxyeicosatrienoic Acids in Humans

Elijovich

Milne

Brown³

et al. 2018

Hypertension

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“…Rats were euthanized at 1,6,24,48,72,120,168, and 336 h after dose administration and QWBA was then carried out on the carcass of n = 1 animal for each time point. A frozen carcass was set in a block of 2% (w/v) aqueous carboxymethyl cellulose at 80°C.…”

Section: Quantitative Whole-body Autoradiography Analysismentioning

confidence: 99%

“…Recent reports indicate that NO 2 -OA promotes beneficial metabolic and anti-inflammatory responses by modulating Nrf2-dependent antioxidant gene expression, sEH activity, and TLR4/NFkB signaling (6)(7)(8). The administration of pure synthetic NO 2 -OA induces beneficial signaling actions and physiological responses in animal models of metabolic, vascular, renal, and pulmonary disease (12).…”

Section: No 2 -Oa Esterification and Metabolism In Adipose Tissue In mentioning

confidence: 99%

“…The electrophilic nature of nitro-alkenes undergoes: 1) reversible Michael DISCUSSION Nitration of unsaturated FAs and the corresponding generation of electrophilic NO 2 -FA occur during acidic conditions of digestion and oxidative inflammatory conditions (3,4,17,18,35). The electrophilic properties of NO 2 -FA induce anti-inflammatory and cytoprotective actions via reversible posttranslational modification of transcriptional regulatory proteins, such as NF-kB, Keap1/ Nrf2, and PPAR-, and enzymes such as xanthine oxidoreductase and sEH (6)(7)(8)(36)(37)(38). Beneficial metabolic and anti-inflammatory effects of NO 2 -FAs have been shown in animal models of fibrosis, atherosclerosis, renal and cardiac ischemia reperfusion, restenosis, and diabetes (12,(39)(40)(41)(42)(43)(44).…”

Section: No 2 -Oa Esterification and Metabolism In Adipose Tissue In mentioning

confidence: 99%

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Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

Fazzari

Khoo

Woodcock

et al. 2017

Journal of Lipid Research

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inflammatory and metabolic stress (1-3). In particular, the reaction between unsaturated FAs and the nitric oxide and nitrite (NO 2  )-derived radical species nitrogen dioxide (·NO 2 ) generates electrophilic FA nitro-alkene byproducts (NO 2 -FAs) (4). These molecules are endogenously detected and have been observed to mediate salutary responses in models of inflammatory injury and oxidative stress. Current data supports that NO 2 -FAs predominantly signal via posttranslational protein modifications, specifically of functionally significant Cys residues of nuclear transcription factor erythroid 2-related factor 2 (Nrf2), soluble epoxide hydrolase (sEH), p65 subunit of nuclear factor kappa B (NF-kB), transient receptor potential cation channel subfamily V member 1 (TRPV1), and heat shock factor-1 (HSF-1) (5-9).NO 2 -FAs have been detected in a variety of species, including mammals and plants, as both free acid and as complex lipid-esterified species (3, 10, 11). For example, NO 2 -FAs are detected at micromolar concentrations in rodent cardiac mitochondria subjected to an episode of ischemia-reperfusion and at nanomolar concentrations in healthy human plasma and urine (12)(13)(14). Additionally, [D 4 ]octadecenoic acid; Nrf2, nuclear transcription factor erythroid 2-related factor 2; OA, oleic acid; PC, phosphatidylcholine; QWBA, quantitative whole-body autoradiography; sEH, soluble epoxide hydrolase; TAG, triacylglyceride. The designations "9-NO 2 -" and "10-NO 2 -"OA are used herein to describe the position of the nitro group in the fatty acid chain and do not refer to IUPAC nomenclature. MED Foundation (M.F.), National Institutes of Health Grants R01-AT006822 (F.J.S.), R01-HL64937, R01-HL132550, and P01-HL103455 (B.A.F.), and American Heart Association Grant 14GRNT20170024 (F.J.S.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the1 To whom correspondence should be addressed. e-mail: freerad@pitt.edu (B.A.F.); fjs2@pitt.edu (F.J.S.) The online version of this article (available at http://www.jlr.org) contains a supplement.

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“…It was found that a combination of green leafy vegetables and olive oil resulted in an increased production of nitro fatty acids, which can lower blood pressure (by blocking epoxide hydrolase) (Charles, 2014). These types of salads are common in the Mediterranean where heart disease is lower than in the rest of Europe.…”

Section: Olive Oil and The Mediterranean Dietmentioning

confidence: 99%

Healthy lifestyles to prevent dementia and reduce dementia symptoms

Hogervorst

2017

WWOP

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Citation: HOGERVOIST, E., 2017 AbstractPurpose Dementia is a growing problem worldwide, due to an ageing population. It has significant human and economic costs. There is no effective medical treatment.Design/methodology Using earlier reviews, we discuss the difference between dementia and cognitive ageing and the different types of dementia, in terms of manifestation and pathology. We reviewed non-modifiable risk factors for dementia, such as age, gender, genetics and education. Education can possibly have lifelong protective effects, as it may promote cognitive reserve. This paper focused on lifestyle interventions to further increase brain reserve capacity. Findings from earlier reviews were summarised to provide guidelines for policymakers and practioners.Findings Our reviews suggested that most nutritional approaches may have limited effectiveness, and should be implemented in midlife, before dementia symptoms are present and probably only in people who are actually nutritionally deficient. We found a reasonable positive evidence base of engagement in cognitive and physical activities to prevent dementia, which may also help reduce symptoms of dementia. Practical and social implicationsFrom the studies reviewed, it was suggested that keeping physically and mentally active may help in all stages of life to prevent, but also reduce dementia symptoms. A focus on nutrition and treating heart disease risk factors is possibly limited to midlife, or before dementia symptoms are present. OrginalityWe used an evidence based approach to review which lifestyle interventions could help prevent dementia or reduce dementia symptoms. The main outcome of this paper was that stage of life and ability (dementia present or not) may interact with success of the intervention

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

Cited by 85 publications

References 52 publications

Two Pools of Epoxyeicosatrienoic Acids in Humans

Two Pools of Epoxyeicosatrienoic Acids in Humans

Nitro-fatty acid pharmacokinetics in the adipose tissue compartment

Healthy lifestyles to prevent dementia and reduce dementia symptoms

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