Epoxy Fatty Acids Are Promising Targets for Treatment of Pain, Cardiovascular Disease and Other Indications Characterized by Mitochondrial Dysfunction, Endoplasmic Stress and Inflammation

McReynolds, Cindy B.; Morisseau, Christophe; Wagner, Karen; Hammock, Bruce D.

doi:10.1007/978-3-030-50621-6_5

Cited by 52 publications

(49 citation statements)

References 136 publications

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“…For epoxide formation, CYP450s effectively oxidize ω-6 fatty acids (arachidonic (ARA) and linoleic (LA) acids) and ω-3 fatty acids (including eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids) at varying rates to produce their respective metabolites, including epoxyoctadeceonic (EpOME), epoxyeicosatrienoic (EpETrE or EET), epoxyeicosatetraenoic (EpETE or EEQ), epoxy-docosapentaenoic (EpDPE or EDP) acids, respectively [ 6 ]. This family of natural compounds, called epoxy-fatty acids (EpFA), act as lipid mediators and are involved in numerous biological and physiological systems including but not limited to regulation of vasotension, inflammation, neuroprotection, cardioprotection, pain sensation, angiogenesis and cellular stress [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Besides EpFAs, sEH metabolizes other natural epoxides such as hepoxilins (HX) or terpene oxides [ 9 ]. Blocking sEH through either a chemical or genetic knockout is effective at increasing EpFA and decreasing their respective dihydroxy-metabolites in a number of tissues and disease models [ 7 , 8 ]. Thus, sEH inhibitors have not only been an effective tool for studying and understanding the role of EpFA in disease states but have also been proposed as therapeutics to be used in treating hypertension, pain and other diseases [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

Morisseau

Kodani

Kamita

et al. 2021

IJMS

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Epoxy-fatty acids (EpFAs) are endogenous lipid mediators that have a large breadth of biological activities, including the regulation of blood pressure, inflammation, angiogenesis, and pain perception. For the past 20 years, soluble epoxide hydrolase (sEH) has been recognized as the primary enzyme for degrading EpFAs in vivo. The sEH converts EpFAs to the generally less biologically active 1,2-diols, which are quickly eliminated from the body. Thus, inhibitors of sEH are being developed as potential drug therapeutics for various diseases including neuropathic pain. Recent findings suggest that other epoxide hydrolases (EHs) such as microsomal epoxide hydrolase (mEH) and epoxide hydrolase-3 (EH3) can contribute significantly to the in vivo metabolism of EpFAs. In this study, we used two complementary approaches to probe the relative importance of sEH, mEH, and EH3 in 15 human tissue extracts: hydrolysis of 14,15-EET and 13,14-EDP using selective inhibitors and protein quantification. The sEH hydrolyzed the majority of EpFAs in all of the tissues investigated, mEH hydrolyzed a significant portion of EpFAs in several tissues, whereas no significant role in EpFAs metabolism was observed for EH3. Our findings indicate that residual mEH activity could limit the therapeutic efficacy of sEH inhibition in certain organs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

Morisseau

Kodani

Kamita

et al. 2021

IJMS

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“…In humans, saturated FAs (palmitic acid, stearic acid) are de novo synthesized by elongation. However, polyunsaturated fatty acids (PUFAs: i.e., linoleic acid, LA (18:2, ∆ 9,12 , ω-6); arachidonic acid, AA (20:4, ∆ 5,8,11,14 , ω-6); alpha-linolenic acid, ALA (18:3, ∆ 9,12,15 , ω-3); docosapentaenoic acid, DPA (22:5, ∆ 4,7,10,13,16 , ω-3); docosahexaenoic acid, DHA (22:6, ∆ 4,7,10,13,16,19 , ω-3); eicosapentaenoic acid, EPA (20:5, ∆ 5,8,11,14,17 , ω-3)) are not produced directly due to the absence of desaturases that introduce a double bond into FAs distal to the ∆9 position. Thus, dietary PUFAs are essential for human beings.…”

Section: Introductionmentioning

confidence: 99%

“…PGs, LTs, and other lipid mediators play physiological and pathophysiological roles via cognate G protein-coupled receptors (GPCRs) [ 7 ]. Because these lipid mediators show pleiotropic functions in a variety of diseases [ 8 , 9 , 10 ], drugs targeting this signaling have been developed, such as non-steroidal anti-inflammatory drugs (NSAIDs; aspirin, indomethacin, and diclofenac for treatment of pain and inflammation) and cysteinyl LT receptor antagonists (montelukast and pranlukast for asthma and allergic rhinitis) [ 9 , 11 , 12 ]. PUFA-derived epoxy FAs (EpFAs including EpETrE; LA-derived epoxy-octadecenoic acid, EpOME; ALA-derived epoxy-octadecadienoic acid, EpODE; DHA-derived epoxy-docosapentaenoic acid, EpDPE; and EPA-derived epoxy-eicosatetraenoic acid, EpETE) show anti-inflammatory effects in treating pain, inflammation, cardiovascular diseases, and other conditions [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

A Soluble Epoxide Hydrolase Inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea, Ameliorates Experimental Autoimmune Encephalomyelitis

Jonnalagadda

Wan

Chun

et al. 2021

IJMS

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Polyunsaturated fatty acids (PUFAs) are essential FAs for human health. Cytochrome P450 oxygenates PUFAs to produce anti-inflammatory and pain-resolving epoxy fatty acids (EpFAs) and other oxylipins whose epoxide ring is opened by the soluble epoxide hydrolase (sEH/Ephx2), resulting in the formation of toxic and pro-inflammatory vicinal diols (dihydroxy-FAs). Pharmacological inhibition of sEH is a promising strategy for the treatment of pain, inflammation, cardiovascular diseases, and other conditions. We tested the efficacy of a potent, selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Prophylactic TPPU treatment significantly ameliorated EAE without affecting circulating white blood cell counts. TPPU accumulated in the spinal cords (SCs), which was correlated with plasma TPPU concentration. Targeted lipidomics in EAE SCs and plasma identified that TPPU blocked production of dihydroxy-FAs efficiently and increased some EpFA species including 12(13)-epoxy-octadecenoic acid (12(13)-EpOME) and 17(18)-epoxy-eicosatrienoic acid (17(18)-EpETE). TPPU did not alter levels of cyclooxygenase (COX-1/2) metabolites, while it increased 12-hydroxyeicosatetraenoic acid (12-HETE) and other 12/15-lipoxygenase metabolites. These analytical results are consistent with sEH inhibitors that reduce neuroinflammation and accelerate anti-inflammatory responses, providing the possibility that sEH inhibitors could be used as a disease modifying therapy, as well as for MS-associated pain relief.

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“…Cytochrome p450 epoxygenases convert C20 and C22 PUFAs, such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid, into C20 and C22 EFAs, such as 5, 6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, 5,6-, 8,9-, 11,12-, 14,15-, and 17,18-epoxyeicosatetraenoic acid, 7,8-, 10,11-, 13,14-, 16,17-, and 19,20epoxydocosapentaenoic acids, respectively (Spector and Kim, 2015). These cytochrome p450 epoxygenasederived EFAs decrease hypertension and pain perception and are involved in homeostasis maintenance and anti-inflammation (McReynolds et al, 2020). Lipoxygenases convert the C20 PUFA arachidonic acid into C20 EFAs, such as 5,6-epoxy-7E ,9E ,11Z ,14Z -eicosatetraenoic acid, which is a pro-inflammatory compound (Jafaru and Justin, 2000), and 8,9-epoxy-5Z ,10E ,12E ,14Z -eicosatetraenoic acid (Kawajiri et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of New Epoxy Fatty Acids from C18 Polyunsaturated Fatty Acids by Linoleate 9-Lipoxygenase from Sphingopyxis macrogoltabida

S¹,

J²,

Oh³

2021

Preprint

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Epoxy fatty acids (EFAs), which exist in the human body, are signaling molecules that maintain homeostasis. They are involved in anti-inflammation and are precursors of dihydroxy fatty acids. EFAs derived from the C20 polyunsaturated fatty acid (PUFA) arachidonic acid by lipoxygenases, such as 5,6-epoxy-7E,9E,11Z,14Z-eicosatetraenoic acid and 8,9-epoxy-5Z,10E,12E,14Z-eicosatetraenoic acid, are found in humans and mice, respectively. However, EFAs derived from C18 PUFAs by lipoxygenases have not been identified to date. In this study, the putative lipoxygenase gene of Spingopyxis macrogoltabida was cloned and expressed in Escherichia coli. The activity and catalytic efficiency (k/K) of the recombinant enzyme were the highest for linoleic acid among the C18 PUFAs, including also α-linolenic acid and γ-linolenic acid. The product obtained from the conversion of linoleic acid by the putative lipoxygenase was identified as 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE) by high-performance liquid chromatography using 9-HODE and 13-hydroxy-9Z,11E-octadecadienoic acid (13-HODE) standards. These results indicate that the enzyme is a linoleate 9-lipoxygenase. The enzyme converted linoleic acid, α-linolenic acid, and γ-linolenic acid into 9-HODE, 13-hydroxy-9Z,11E,15Z-octadecatrienoic acid, and 9-hydroxy-6Z,10E,12Z-octadecatrienoic acid, respectively. Moreover, the enzyme also converted the three C18 PUFAs into 9,10-epoxy-11E,13E-octadecadienoic acid, 12,13-epoxy-8E,10E,15Z-octadecatrienoic acid, and 9,10-epoxy-6Z,11E,13E-octadecatrienoic acid, respectively, which were identified as new EFAs by liquid chromatography-mass spectrometry/mass spectrometry. To our knowledge, this is the first report on the biosynthesis of EFAs from C18 PUFAs via a lipoxygenase.

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Epoxy Fatty Acids Are Promising Targets for Treatment of Pain, Cardiovascular Disease and Other Indications Characterized by Mitochondrial Dysfunction, Endoplasmic Stress and Inflammation

Cited by 52 publications

References 136 publications

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

Relative Importance of Soluble and Microsomal Epoxide Hydrolases for the Hydrolysis of Epoxy-Fatty Acids in Human Tissues

A Soluble Epoxide Hydrolase Inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea, Ameliorates Experimental Autoimmune Encephalomyelitis

Biosynthesis of New Epoxy Fatty Acids from C18 Polyunsaturated Fatty Acids by Linoleate 9-Lipoxygenase from Sphingopyxis macrogoltabida

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