Therapeutic potential of omega-3 fatty acid-derived epoxyeicosanoids in cardiovascular and inflammatory diseases

Schunck, Wolf‐Hagen; Konkel, Anne; Fischer, Robert; Weylandt, Karsten H.

doi:10.1016/j.pharmthera.2017.10.016

Cited by 180 publications

(170 citation statements)

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“…[32][33][34]63 A potential advantage of EET analogues is that they directly compensate for an EET deficiency. 36 In contrast, the beneficial effects of sEH inhibitors largely depend on endogenous EET production and, thus, on the expression and activity of CYP epoxygenases under the given pathological conditions. Providing first evidence for their therapeutic potential, synthetic EET analogues rescued the metabolic syndrome phenotype of HO-2-null mice, 64 prevented adiposity and vascular dysfunction in rats fed a high fat diet, 65 attenuated cisplatin nephrotoxicity 66 in rats, and decreased renal inflammation and injury in ANG II hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphorylation of Akt at Ser-473 is essential for stabilization of actin cytoskeleton 56 and endothelial viability in response to hypoxic stress. 36 In contrast, the beneficial effects of sEH inhibitors largely depend on endogenous EET production and, thus, on the expression and activity of CYP epoxygenases under the given pathological conditions. 58 Our data also show that the EET analogue significantly reduced I/R-induced inflammatory cell infiltration.…”

Section: Circulating Cyp-eicosanoids In Patients Who Do or Do Not Dmentioning

confidence: 99%

“…21 EET-mediated prevention of hypoxia/reoxygenation-induced apoptosis and cell death has been demonstrated in endothelial cells and cardiomyocytes. [32][33][34][35][36] In the present study, we tested the hypothesis that synthetic EET analogues may protect the kidney against I/R-induced AKI. [25][26][27][28] Induction or transgenic overexpression of EET-generating CYP enzymes attenuated renal injury in rat and mouse models of angiotensin II-induced hypertension.…”

Section: Introductionmentioning

confidence: 99%

“…31 SEH-inhibitors and most recently also metabolically robust synthetic EET analogues are under development that may provide novel therapeutic options for the treatment of cardiovascular and renal disease. [32][33][34][35][36] In the present study, we tested the hypothesis that synthetic EET analogues may protect the kidney against I/R-induced AKI. Experiments were performed in uninephrectomized Lewis rats, a model that partially mimics the situation after renal transplantation.…”

Section: Introductionmentioning

confidence: 99%

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A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury

et al. 2019

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Aim: Imbalances in cytochrome P450 (CYP)-dependent eicosanoid formation may play a central role in ischemic acute kidney injury (AKI). We reported previously that inhibition of 20-hydroxyeicosatetraenoic acid (20-HETE) action ameliorated ischemia/reperfusion (I/R)-induced AKI in rats. Now we tested the hypothesis that enhancement of epoxyeicosatrienoic acid (EET) actions may counteract the detrimental effects of 20-HETE and prevent the initiation of AKI. Methods: Male Lewis rats underwent right nephrectomy and ischemia was induced by 45 min clamping of the left renal pedicle followed by up to 48 h of reperfusion.Circulating CYP-eicosanoid profiles were compared in patients who underwent cardiac surgery with (n = 21) and without (n = 38) developing postoperative AKI. Results: Ischemia induced an about eightfold increase of renal 20-HETE levels, whereas free EETs were not accumulated. To compensate for this imbalance, a synthetic 14,15-EET analogue was administered by intrarenal infusion before ischemia.The EET analogue improved renal reoxygenation as monitored by in vivo parametric MRI during the initial 2 h reperfusion phase. The EET analogue improved PI3Kas well as mTORC2-dependent rephosphorylation of Akt, induced inactivation of GSK-3β, reduced the development of tubular apoptosis and attenuated inflammatory cell infiltration. The EET analogue also significantly alleviated the I/R-induced drop

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Section: Discussionmentioning

confidence: 99%

Section: Circulating Cyp-eicosanoids In Patients Who Do or Do Not Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury

et al. 2019

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“…To add to the complexity of lipid metabolism, cytochromes P450 (CYPs) are known to epoxidize lipids into anti-inflammatory and anti-pain mediators that are more effective than the parent molecules. For example, CYPs convert AA and omega-3 PUFAs into epoxy-PUFAs that have been shown to decrease pain [53][54][55] . Recently, the CYP-mediated metabolism of eCBs was shown to produce epoxy-eCBs that exhibit CB2 receptor selectivity and are anti-inflammatory and anti-tumorigenic [56][57][58] .…”

Section: Introductionmentioning

confidence: 99%

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

Arnold

Carnevale

Xie³

et al. 2020

Preprint

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The endocannabinoid (eCB) system is a promising target to mitigate pain as the eCBs are endogenous ligands of the pain-mediating receptors-cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Here we report on a novel class of lipids formed by the epoxidation of Narachidonoyl-dopamine (NADA) and N-arachidonoyl serotonin (NA5HT) by cytochrome P450 (CYP) epoxygenases. These epoxides (epoNADA and epoNA5HT) are dual-functional rheostat modulators (varying strength of agonism or antagonism) of the eCB-TRPV1 axis. In fact, epoNADA is a 6-fold stronger agonist of TRPV1 than NADA while epoNA5HT is a 30-fold stronger antagonist of TRPV1 than NA5HT and displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. The epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1β, TNF-α and nitrous oxide (NO) and raise anti-inflammatory IL-10 in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of another eCB, anandamide (AEA). We provide evidence for the direct biochemical mechanism of this potentiation using human CYP2J2, a CYP epoxygenase in the human brain, using detailed kinetics studies and molecular dynamics simulations. Taken all together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by CYP epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are more potent, multi-faceted endogenous molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors. The identification of these molecules will serve as templates for the synthesis of new multi-target therapeutics for the treatment of inflammatory pain.

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Dietary Lipids and Health

Morzelle¹,

Watkins²,

Li³

et al. 2020

Bailey's Industrial Oil and Fat Products

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Lipids are essential components of living organisms and support multiple biological and physiological functions in the human body. They serve as the structural building material of all membranes of cells and organelles. Lipids and their derivatives also serve as signaling molecules that facilitate a variety of physiological functions. In addition, lipids are recognized as important biomarkers of disease and are involved in several pathological conditions. Individual fatty acids can influence biological processes, such as membrane‐associated receptors and signal transduction systems, and ion channels. Recent literature also demonstrates a specific role of fatty acids in gene modulation and protein expression to influence risk of chronic disease. Polyunsaturated fatty acids (PUFAs) are the focus of substantial research interest in this area mainly because of their ability to be converted to various bioactive regulatory molecules, such as prostaglandins, leukotrienes, and thromboxanes. Arachidonic acid (AA, 20:4n‐6) and eicosapentaenoic acid (EPA, 20:5n‐3) are two major players in the regulation and production of these bioactive molecules. In addition, an absolute requirement of docosahexaenoic acid (DHA) is necessary for normal neural and retinal development in the infant and young child. Besides the study of these PUFA molecules, numerous animal and human studies also suggest that other dietary lipids, such as cholesterol and saturated fatty acids, increase serum cholesterol as well as LDL‐cholesterol concentrations. In summary, this article provides a contemporary understanding of food lipids in nutrition and health, especially the underlying cellular and molecular mechanisms of the actions of these bioactive dietary lipids.

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Therapeutic potential of omega-3 fatty acid-derived epoxyeicosanoids in cardiovascular and inflammatory diseases

Cited by 180 publications

References 340 publications

A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury

A synthetic epoxyeicosatrienoic acid analogue prevents the initiation of ischemic acute kidney injury

Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel

Dietary Lipids and Health

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