Soluble Epoxide Hydrolase Inhibitors Reduce the Development of Atherosclerosis in Apolipoprotein E-Knockout Mouse Model

Ulu, Arzu; Davis, Benjamin B.; Tsai, Hui‐Jen; Kim, In Hae; Morisseau, Christophe; Inceoglu, Bora; Fiehn, Oliver; Hammock, Bruce D.; Weiss, Robert H.

doi:10.1097/fjc.0b013e318185fa3c

Cited by 115 publications

(115 citation statements)

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“…Therefore, considerable interest has arisen in developing methods to enhance the bioavailability of EETs by inhibiting sEH. As expected, inhibition of sEH prevents several cardiovascular diseases, including high blood pressure, cardiac fibrosis, inflammation, and atherosclerosis (16,19,24). Therefore, the enzyme activity of sEH appears to play an important role in the development of cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

“…Soluble epoxide hydrolase (sEH) metabolizes EETs to their corresponding dihydroxyeicosatrienoic acids, which limits the availability of EETs (16). Several models of atherosclerosis have suggested that inhibition of sEH, with an ensuing decrease in EET degradation, may attenuate atherosclerosis development and aneurysm formation (3,14,15,19,25). Treatment with sEH inhibitors also attenuated cardiohypertrophy in rats with angiotensin II treatment and in a murine model with transverse aortic constriction (21).…”

Section: In This Study We Found That Soluble Epoxide Hydrolase (Seh)mentioning

confidence: 99%

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Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration

Wang

Huo

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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. Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration. Am J Physiol Heart Circ Physiol 309: H1894 -H1903, 2015. First published October 9, 2015; doi:10.1152/ajpheart.00289.2015.-Epoxyeicosatrienoic acids (EETs) have beneficial effects on cardiovascular disease. Soluble epoxide hydrolase (sEH) metabolizes EETs to less active diols, thus diminishing their biological activity. sEH inhibitors can suppress the progression of atherosclerotic lesions in animal models. However, the regulation of sEH in vascular smooth muscle cells (VSMCs) and role of sEH in patients with atherosclerosis have not been evaluated. We hypothesize that sEH in VSMCs plays a pivotal role in atherosclerosis and injury-induced neointima formation. In this study, sEH expression in human autopsy atherosclerotic plaque was determined by immunohistochemistry. In cultured rat and human VSMCs, the phenotypic switching marker and sEH expression induced by plateletderived growth factor-BB (PDGF-BB) were examined by Western blot analysis. Carotid-artery balloon injury was performed after adenovirus-mediated overexpression of sEH or oral administration of a potent sEH inhibitor in Sprague-Dawley rats. sEH was highly expressed in VSMCs of the intima and media within human atherosclerotic plaque. In vitro, PDGF-BB upregulated the expression in VSMCs after transcription and promoted cell proliferation and migration; the latter effect could be largely attenuated by an sEH inhibitor. Adenovirus-mediated overexpression of sEH could mimic the effect of PDGF-BB and induce VSMC proliferation and migration. In vivo, the sEH inhibitor led to a significant decrease in injury-induced neointima formation in a rat carotid-artery injury model. These data establish the effect of sEH expression on atherosclerotic progression and vascular remodeling after injury, thus identifying a novel integrative role for sEH in VSMC phenotypic modulation and migration. Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular occlusive disease.

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Section: Discussionmentioning

confidence: 99%

Section: In This Study We Found That Soluble Epoxide Hydrolase (Seh)mentioning

confidence: 99%

Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration

Wang

Huo

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…During preparation of this manuscript, Ulu et al reported that an s-EH inhibitor, AEPU, also reduced the development of atherosclerosis in Ang II-treated apoE-deficient mice, which is consistent with the present results. 16 However, they found that AEPU did not reduce the plasma cholesterol levels. It could be attributable to the compound specific activity or the animals' failure to develop hyperlipidemia in this study, which is rare in atherogenic diet-fed apoE-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

Zhang

Vincelette

Cheng

et al. 2009

ATVB

106

107

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Objective-Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects. Methods and Results-Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1␣, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall. Key Words: epoxyeicosatrienoic acids Ⅲ soluble epoxide hydrolase Ⅲ dyslipidemia Ⅲ atherosclerosis Ⅲ abdominal aorta aneurysm Ⅲ inflammatory markers A rachidonic acid can be metabolized by 3 major oxidative pathways: cyclooxygenase (COX) forming prostaglandins; lipoxygenase (LOX) forming hydroxyeicosatetraenoic acids (HETEs) and leukotrienes; and cytochrome P-450 monooxygenase forming epoxides and HETEs. 1 The COX and LOX pathways have been extensively studied, and their eicosanoid products have been shown to play important roles in a variety of biological processes such as inflammation, cell proliferation, and intracellular signaling. In contrast, less is known about the "third pathway" of arachidonic acid metabolism. Recently, epoxyeicosatrienoic acids (EETs), the cytochrome P450 metabolites of arachidonic acid, have received increasing attention for multiple beneficial biological functions, including vasodilation, antiinflammation, and inhibition of proliferation and migration of vascular smooth muscle cells. 1,2 Based on these properties, it has been postulated that EETs may exert therapeutic benefits in inflammatory vascular diseases, such as atherosclerosis. 2,3 Soluble epoxide hydrolase (s-EH) converts EETs into their corresponding dihydroxyeicosatrienoic acids (DHETs), which are generally thought to have reduced biological activity relative to EETs, and hydration of the EETs by s-EH is a dominant mechanism whereby their activity can be reduced. 4 Thus, inhibition of s-EH could be a promising therapeutic target for amplifying the beneficial effects of EETs. 4 Indeed, s-EH inhibitors have been demonstrated to lower blood pressure in hypertension, 5,6 decrease hypertension-induced renal damage 7 and cerebral ischemia injury, 8 attenuate vascular smooth muscle cell proliferation, 9 and reduce tissue...

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“…There has been great recent interest in the therapeutic potential of sEH inhibitors as novel antiinflammatories. sEH inhibitors or genetic disruption of sEH in mice reduces inflammation in models of endotoxin-induced pulmonary inflammation (22), ischemia-reperfusion injury (33,34), subarachnoid hemorrhage (35), and the murine ovalbumin model of asthma (36), and in more chronic models including atherogenic diet-induced fatty liver disease and adipose tissue (37) and atherosclerosis (38,39). In contrast, the expression and roles of epoxy-oxylipins during inflammatory resolution have not been investigated.…”

Section: Discussionmentioning

confidence: 99%

CYP450-derived oxylipins mediate inflammatory resolution

Gilroy

Edin

Maeyer

et al. 2016

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

121

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Resolution of inflammation has emerged as an active process in immunobiology, with cells of the mononuclear phagocyte system being critical in mediating efferocytosis and wound debridement and bridging the gap between innate and adaptive immunity. Here we investigated the roles of cytochrome P450 (CYP)-derived epoxy-oxylipins in a well-characterized model of sterile resolving peritonitis in the mouse. Epoxy-oxylipins were produced in a biphasic manner during the peaks of acute (4 h) and resolution phases (24-48 h) of the response. The epoxygenase inhibitor SKF525A (epoxI) given at 24 h selectively inhibited arachidonic acid-and linoleic acid-derived CYP450-epoxy-oxlipins and resulted in a dramatic influx in monocytes. The epoxI-recruited monocytes were strongly GR1 hi and Ly6c lo monocytes, resident macrophages, and recruited dendritic cells all showed a dramatic change in their resolution signature following in vivo epoxI treatment. Markers of macrophage differentiation CD11b, MerTK, and CD103 were reduced, and monocyte-derived macrophages and resident macrophages ex vivo showed greatly impaired phagocytosis of zymosan and efferocytosis of apoptotic thymocytes following epoxI treatment. These findings demonstrate that epoxy-oxylipins have a critical role in monocyte lineage recruitment and activity to promote inflammatory resolution and represent a previously unidentified internal regulatory system governing the establishment of adaptive immunity.oxylipins | resolution | monocyte | phagocytosis | epoxygenase M onocytes and monocyte-derived macrophages play a critical role in chronic inflammation, in part via the production and release of lipid mediators (1). One such lipid precursor, arachidonic acid, is metabolized into families of biologically active mediators by the cyclooxygenase, lipoxygenase, and cytochrome P450 (CYP) pathways (2, 3). CYPs metabolize arachidonic acid by: (i) an epoxygenase activity that catalyzes the conversion of arachidonic acid to epoxyeicosatrienoic acids (EETs); (ii) a lipoxygenase-like activity that metabolizes arachidonic acid to midchain hydroxyeicosatetraenoic acids (HETEs); and (iii) ω-and ω-1-hydroxylase activity, which produces ω-terminal HETEs (3). In addition to arachidonic acid, CYPs with epoxygenase activity can also metabolize alternative polyunsaturated fatty acids such as linoleic acid and docosahexaenoic acid into a series of products including epoxyoctadacamonoenoic acids (EpOMEs) and 19,20-epoxydocosapentaenoic acid (EpDPE), respectively, whose functions remain poorly understood (3-5).The main polyunsaturated fatty acid-metabolizing CYPs belong to the CYP2 family, in particular the CYP2J and CYP2C subfamilies (3, 4, 6, 7). Moreover, these CYP-lipid-metabolizing enzymes are the primary sources of eicosanoids in small blood vessels, the kidney, liver, lung, intestines, heart, and pancreas (3, 7). In most organs, EETs and related epoxygenase products are metabolically unstable and are rapidly metabolized. The major pathway that regulates EET metabolism is that catalyzed...

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Soluble Epoxide Hydrolase Inhibitors Reduce the Development of Atherosclerosis in Apolipoprotein E-Knockout Mouse Model

Cited by 115 publications

References 35 publications

Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration

Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration

Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

CYP450-derived oxylipins mediate inflammatory resolution

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