Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice

Roche, Colette; Besnier, Marie; Cassel, R.; Harouki, Najah; Coquerel, David; Guerrot, Dominique; Nicol, Lionel; Loizon, Emmanuelle; Rémy-Jouet, Isabelle; Morisseau, Christophe; Mulder, Paul; Ouvrard‐Pascaud, Antoine; Madec, Anne Marie; Richard, Vincent; Bellien, Jérémy

doi:10.1152/ajpheart.00465.2014

Cited by 45 publications

(43 citation statements)

References 27 publications

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“…Therefore, reduced levels of these beneficial LMs, in particular EETs and EDPs, may contribute to the adverse effects of obesity. This is supported by recent studies, which have shown that pharmacological inhibition or transgenic deletion of sEH, which is the dominant enzyme in degrading fatty acid epoxides, protected mice from various adverse consequences of obesity, such as endoplasmic reticulum stress, metabolic syndrome, hepatic steatosis, inflammation, and endothelial dysfunction (11,(14)(15)(16)(17)(18)(19)(20)(21). Together, these results strongly support that CYP-derived fatty acid epoxides play important roles in regulating the pathology of obesity.…”

Section: Discussionsupporting

confidence: 67%

“…HFD feeding also reduced levels of CYP‐derived epoxyeicosatrienoic acids (EETs), which have potent anti‐inflammatory, vasodilative, and cardioprotective effects . Pharmacological inhibition or transgenic deletion of soluble epoxide hydrolase (sEH, the dominant enzyme in degrading EETs) has been shown to protect mice from various adverse effects induced by obesity . Together, these results support that LMs play critical roles in regulating the pathology of obesity.…”

Section: Introductionmentioning

confidence: 87%

“…Most previous studies of LMs in obesity have only studied single or limited numbers of LMs (9,10,(14)(15)(16)(17)(18)(19)(20)(21). However, the enzymatic metabolism of PUFAs produces hundreds of LMs, which could have different or even opposite biological activities, it would be difficult to understand the biological processes by only studying single or limited number of LMs (22).…”

Section: Introductionmentioning

confidence: 99%

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Lipidomic profiling of high‐fat diet‐induced obesity in mice: Importance of cytochrome P450‐derived fatty acid epoxides

Wang

Yang

et al. 2016

Obesity

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Objective: Enzymatic metabolism of polyunsaturated fatty acids leads to formation of bioactive lipid metabolites (LMs). Previous studies have shown that obesity leads to deregulation of LMs in adipose tissues. However, most previous studies have focused on a single or limited number of LMs, and few systematical analyses have been carried out. Methods: A LC-MS/MS-based lipidomics approach was used, which can analyze >100 LMs produced by cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) enzymes, to analyze the profile of LMs in high-fat diet-induced obesity in mice. Results: LC-MS/MS showed that high-fat feeding significantly modulated profiles of LMs in adipose tissues. Among the three major polyunsaturated fatty acid metabolizing pathways (cyclooxygenase, lipoxygenase, and CYP), CYP-derived fatty acid epoxides were the most dramatically altered LMs. Almost all types of fatty acid epoxides were reduced by 70% to 90% in adipose tissues of high-fat diet-fed mice. Consistent with the reduced levels of fatty acid epoxides, the gene expression of several CYP epoxygenases, including Cyp2j5, Cyp2j6, and Cyp2c44, was significantly reduced in adipose tissues of high-fat diet-fed mice. Conclusions: Results show that CYP-derived fatty acid epoxides are the most responsive LMs in highfat diet-induced obesity, suggesting that these LMs could play critical roles in obesity.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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Lipidomic profiling of high‐fat diet‐induced obesity in mice: Importance of cytochrome P450‐derived fatty acid epoxides

Wang

Yang

et al. 2016

Obesity

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“…, Roche et al . ); (iv) upregulation of G protein‐coupled receptor kinase 2 (GRK2) (Taguchi et al . ); (v) overexpression of protein kinase C‐ β (PKC β ) and induction of ET‐1 expression in the endothelium (Lu et al .…”

Section: Nitric Oxidementioning

confidence: 99%

Endothelial dysfunction and vascular disease - a 30th anniversary update

Vanhoutte¹,

et al. 2016

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The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H O ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive G (e.g. responses to α -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive G (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H O ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

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“…Previous studies showed that the tissue levels of COX-derived prostaglandin E 2 (PGE 2 ) and LOX-derived leukotriene B 4 (LTB 4 ) are increased in adipose tissues of obese subjects (15,16). Besides the intensively studied COX and LOX pathways, recent research showed that soluble epoxide hydrolase (sEH), which is the enzyme that converts CYP-produced fatty acid epoxides to the corresponding fatty acid diols, is up-regulated in liver and adipose tissues of obese animals, and could contribute to various obesity-induced disorders (14,(17)(18)(19)(20)(21)(22)(23)(24). However, the roles of eicosanoid signaling in obesity-induced colonic inflammation are unknown.…”

mentioning

confidence: 99%

Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation

Wang

Yang

Zhang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is associated with enhanced colonic inflammation, which is a major risk factor for colorectal cancer. Considering the obesity epidemic in Western countries, it is important to identify novel therapeutic targets for obesity-induced colonic inflammation, to develop targeted strategies for prevention. Eicosanoids are endogenous lipid signaling molecules involved in regulating inflammation and immune responses. Using an LC-MS/MS-based lipidomics approach, we find that obesity-induced colonic inflammation is associated with increased expression of soluble epoxide hydrolase (sEH) and its eicosanoid metabolites, termed fatty acid diols, in colon tissue. Furthermore, we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols, attenuates obesity-induced colonic inflammation, and decreases obesity-induced activation of Wnt signaling in mice. Together, these results support that sEH could be a novel therapeutic target for obesity-induced colonic inflammation and associated diseases.

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Soluble epoxide hydrolase inhibition improves coronary endothelial function and prevents the development of cardiac alterations in obese insulin-resistant mice

Cited by 45 publications

References 27 publications

Lipidomic profiling of high‐fat diet‐induced obesity in mice: Importance of cytochrome P450‐derived fatty acid epoxides

Lipidomic profiling of high‐fat diet‐induced obesity in mice: Importance of cytochrome P450‐derived fatty acid epoxides

Endothelial dysfunction and vascular disease - a 30th anniversary update

Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation

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