Soluble Epoxide Hydrolase Gene Deletion Is Protective Against Experimental Cerebral Ischemia

Zhang, Wenri; Otsuka, Takashi; Sugo, Nobuo; Ardeshiri, Ardi; Alhadid, Yazan; Iliff, Jeffrey J.; DeBarber, Andrea E.; Koop, Dennis R.; Alkayed, Nabil J.

doi:10.1161/strokeaha.107.508325

Cited by 156 publications

(189 citation statements)

References 30 publications

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“…48,49 Moreover, mice that had the gene responsible for SEH production deleted also were protected from cerebral ischemic reperfusion injury. 50 Based on our current findings and published findings in the Ephx2 Ϫ/Ϫ mice, we conclude that the protection from cerebral ischemia with AUDA treatment is most likely to be attributable to SEH inhibition.…”

Section: Discussionsupporting

confidence: 65%

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Simpkins

Rudic

Schreihofer

et al. 2009

The American Journal of Pathology

100

118

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Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-ylureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive WistarKyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDAtreated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke. Epoxyeicosatrienoic acids (EETs), lipid metabolites produced from arachidonic acid by CYP450 enzymes, are novel mediators that antagonize the sequela of hypertension, 1 match cerebral blood flow to increased neural activity and metabolic demand, promotes angiogenesis, 2 and protect against ischemia.3,4 Because ischemic stroke occurs with loss of cerebral blood flow and is strongly associated with hypertension, modulation of epoxide degradation has potential in managing ischemic stroke. Unfortunately, pharmacological utility of exogenous EETs is impractical because the epoxides are rapidly degraded by the soluble epoxide hydrolase (SEH) into their less active diol, dihydroxyeicosatrienoic acids. 5In fact, human SEH polymorphisms are linked to the incidence of ischemic stroke, 6 and this association could be related to modifications in SEH activity, and thus epoxide catabolism. 7 An alternative strategy that has been used to increase EETs systemically is SEH inhibition. 1 We previously showed that the SEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects against cerebral ischemia in spontaneously hypertensive stroke-prone (SHRSP) rats, an animal model of essential hypertension.8 Interestingly, chronic AUDA treatment in SHRSP rats effectively decreased infarct size induced by middle cerebral artery occlusion (MCAO)

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Section: Discussionsupporting

confidence: 65%

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Simpkins

Rudic

Schreihofer

et al. 2009

The American Journal of Pathology

100

118

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“…The neuropil in the brain consists mainly of unmyelinated axons, dendrites, and glial cell processes. Because EETs are potent vasodilators and have been shown to be neuroprotective (Zhang et al, 2008), neural CYP2J8 expression may be involved in CYP2J2 17 19 14 7 10 20 13 CYP2J5 1 1 18 0 10 23 47 CYP2J6 2 1 34 8 11 25 20 CYP2J8 7 28 9 18 8 21 9 CYP2J9 3 1 33 11 12 25 14 CYP2J11 11 1 28 2 11 24 23 CYP2J12 2 1 35 4 13 21 26 CYP2J13 22 28 13 3 7 13 14 Fig. 5.…”

Section: Discussionmentioning

confidence: 99%

“…AA, a polyunsaturated fatty acid present in mammalian cell membranes, is metabolized by multiple P450s into epoxyeicosatrienoic acids (EETs), midchain hydroxyeicosatetraenoic acids (HETEs), and v-terminal HETEs (Capdevila et al, 2000;Kroetz and Zeldin, 2002;Nebert and Russell, 2002). EETs have substantial vasodilatory (Campbell et al, 1996;Larsen et al, 2006), anti-inflammatory (Node et al, 1999), fibrinolytic (Node et al, 2001), cardioprotective (Seubert et al, 2004;Seubert et al, 2006), and angiogenic (Wang et al, 2005) effects both in vitro and in vivo, and provide protection from ischemia in brain, heart, and lung models (Seubert et al, 2007;Zhang et al, 2008;Townsley et al, 2010). EET levels are regulated by both synthesis and breakdown.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Four New Mouse Cytochrome P450 Enzymes of the CYP2J Subfamily

et al. 2013

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The cytochrome P450 superfamily encompasses a diverse group of enzymes that catalyze the oxidation of various substrates. The mouse CYP2J subfamily includes members that have wide tissue distribution and are active in the metabolism of arachidonic acid (AA), linoleic acid (LA), and other lipids and xenobiotics. The mouse Cyp2j locus contains seven genes and three pseudogenes located in a contiguous 0.62 megabase cluster on chromosome 4. We describe four new mouse CYP2J isoforms (designated CYP2J8, CYP2J11, CYP2J12, and CYP2J13). The four cDNAs contain open reading frames that encode polypeptides with 62-84% identity with the three previously identified mouse CYP2Js. All four new CYP2J proteins were expressed in Sf21 insect cells. Each recombinant protein metabolized AA and LA to epoxides and hydroxy derivatives. Specific antibodies, mRNA probes, and polymerase chain reaction primer sets were developed for each mouse CYP2J to examine their tissue distribution. CYP2J8 transcripts were found in the kidney, liver, and brain, and protein expression was confirmed in the kidney and brain (neuropil). CYP2J11 transcripts were most abundant in the kidney and heart, with protein detected primarily in the kidney (proximal convoluted tubules), liver, and heart (cardiomyocytes). CYP2J12 transcripts were prominently present in the brain, and CYP2J13 transcripts were detected in multiple tissues, with the highest expression in the kidney. CYP2J12 and CYP2J13 protein expression could not be determined because the antibodies developed were not immunospecific. We conclude that the four new CYP2J isoforms might be involved in the metabolism of AA and LA to bioactive lipids in mouse hepatic and extrahepatic tissues.

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“…Finally, EETs play an important role in the blood flow response to cerebral ischemia. Inhibition of sEH results in a reduction of ischemic damage in a mouse model of experimental stroke and is associated with elevated cortical blood flow during vascular occlusion (35,36).…”

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confidence: 99%

Epoxyeicosanoids as mediators of neurogenic vasodilation in cerebral vessels

Iliff¹,

Wang²,

Zeldin

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Iliff JJ, Wang R, Zeldin DC, Alkayed NJ. Epoxyeicosanoids as mediators of neurogenic vasodilation in cerebral vessels. Am J Physiol Heart Circ Physiol 296: H1352-H1363, 2009. First published March 20, 2009 doi:10.1152/ajpheart.00950.2008 are potent vasodilators produced from arachidonic acid by cytochrome P-450 (CYP) epoxygenases and metabolized to vicinal diols by soluble epoxide hydrolase (sEH). In the brain, EETs are produced by astrocytes and the vascular endothelium and are involved in the control of cerebral blood flow (CBF). Recent evidence, however, suggests that epoxygenases and sEH are present in perivascular vasodilator nerve fibers innervating the cerebral surface vasculature. In the present study, we tested the hypothesis that EETs are nervederived relaxing factors in the cerebral circulation. We first traced these fibers by retrograde labeling in the rat to trigeminal ganglia (TG) and sphenopalatine ganglia (SPG). We then examined the expression of CYP epoxygenases and sEH in these ganglia. RT-PCR and Western blot analysis identified CYP2J3 and CYP2J4 epoxygenase isoforms and sEH in both TG and SPG, and immunofluorescence double labeling identified CYP2J and sEH immunoreactivity in neuronal cell bodies of both ganglia. To evaluate the functional role of EETs in neurogenic vasodilation, we elicited cortical hyperemia by electrically stimulating efferent cerebral perivascular nerve fibers and by chemically stimulating oral trigeminal fibers with capsaicin. Cortical blood flow responses were monitored by laser-Doppler flowmetry. Local administration to the cortical surface of the putative EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid (30 mol/l) attenuated CBF responses to electrical and chemical stimulation. These results suggest that EETs are produced by perivascular nerves and play a role in neurogenic vasodilation of the cerebral vasculature. The findings have important implications to such clinical conditions as migraine, vasospasm after subarachnoid hemorrhage, and stroke. cerebral blood flow regulation; cytochrome P-450 epoxygenase; epoxyeicosatrienoic acid; soluble epoxide hydrolase; perivascular nerves EPOXYEICOSATRIENOIC ACIDS (EETs) are potent vasodilators and important regulators of vascular function that are synthesized from arachidonic acid by cytochrome P-450 (CYP) epoxygenase enzymes of the CYP2C and CYP2J families (10,24,33). The enzyme soluble epoxide hydrolase (sEH) is the dominant route of EET degradation, catalyzing their metabolism to dihydroxyeicosatrienoic acids (9). In the brain, EETs are known to be released from astrocytes and the vascular endothelium (3, 18). They directly dilate cerebral arteries (4, 8) and exert regulatory control over several facets of vascular function, including angiogenesis (19, 34) and platelet adhesion (14). EETs are key regulators of cerebral blood flow (CBF), mediating neurovascular coupling in the intact brain (2,20,21). Finally, EETs play an important role in the blood flow response to cerebral ischemia. Inhibition of sEH results in a reducti...

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Soluble Epoxide Hydrolase Gene Deletion Is Protective Against Experimental Cerebral Ischemia

Cited by 156 publications

References 30 publications

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Characterization of Four New Mouse Cytochrome P450 Enzymes of the CYP2J Subfamily

Epoxyeicosanoids as mediators of neurogenic vasodilation in cerebral vessels

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