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The Journal of Neuroscience, April 25, 2007, 27(17):4642-4649; doi:10.1523/JNEUROSCI.0056-07.2007

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Neurobiology of Disease
Polymorphisms in the Human Soluble Epoxide Hydrolase Gene EPHX2 Linked to Neuronal Survival after Ischemic Injury

Ines P. Koerner,¹ Rachel Jacks,¹ Andrea E. DeBarber,² Dennis Koop,² Peizhong Mao,³ David F. Grant,⁴ and Nabil J. Alkayed^1,2

¹Departments of Anesthesiology and Peri-Operative Medicine, ²Physiology and Pharmacology, and ³Public Health and Preventive Medicine, Oregon Health & Science University, Portland, Oregon 97239-3098, and ⁴Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269

Correspondence should be addressed to Dr. Nabil J. Alkayed, Associate Professor, Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, UHS-2, Portland, OR 97239-3098. Email: alkayedn{at}ohsu.edu

Single nucleotide polymorphisms (SNPs) in the human EPHX2 gene have recently been implicated in susceptibility to cardiovascular disease, including stroke. EPHX2 encodes for soluble epoxide hydrolase (sEH), an important enzyme in the metabolic breakdown of arachidonic acid-derived eicosanoids referred to as epoxyeicosatrienoic acids (EETs). We previously demonstrated that EETs are protective against ischemic cell death in culture. Therefore, we tested the hypothesis that polymorphisms in the human EPHX2 gene alter sEH enzyme activity and affect neuronal survival after ischemic injury in vitro. Human EPHX2 mutants were recreated by site-directed mutagenesis and fused downstream of TAT protein transduction domain. Western blot analysis and immunocytochemistry staining revealed high-transduction efficiency of human TAT-sEH variants in rat primary cultured cortical neurons, associated with increased metabolism of 14,15-EET to corresponding 14,15-dihydroxyeicosatrienoic acid. A human variant of sEH with Arg103Cys amino acid substitution, previously demonstrated to increase sEH enzymatic activity, was associated with increased cell death induced in cortical neurons by oxygen-glucose deprivation (OGD) and reoxygenation. In contrast, the Arg287Gln mutation was associated with reduced sEH activity and protection from OGD-induced neuronal cell death. We conclude that sequence variations in the human EPHX2 gene alter susceptibility to ischemic injury and neuronal survival in a manner linked to changes in the hydrolase activity of the enzyme. The findings suggest that human EPHX2 mutations may in part explain the genetic variability in sensitivity to ischemic brain injury and stroke outcome.

Key words: EETs; neuroprotection; stroke; ischemia; eicosanoids; protein transduction domain; P450 epoxygenase

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Received Sept. 25, 2006; revised March 20, 2007; accepted March 22, 2007.

Correspondence should be addressed to Dr. Nabil J. Alkayed, Associate Professor, Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, UHS-2, Portland, OR 97239-3098. Email: alkayedn{at}ohsu.edu

This article has been cited by other articles:

				W. Zhang, T. Otsuka, N. Sugo, A. Ardeshiri, Y. K. Alhadid, J. J. Iliff, A. E. DeBarber, D. R. Koop, and N. J. Alkayed Soluble Epoxide Hydrolase Gene Deletion Is Protective Against Experimental Cerebral Ischemia Stroke, July 1, 2008; 39(7): 2073 - 2078. [Abstract] [Full Text] [PDF]

				P. Sura, R. Sura, A. E. EnayetAllah, and D. F. Grant Distribution and Expression of Soluble Epoxide Hydrolase in Human Brain J. Histochem. Cytochem., June 1, 2008; 56(6): 551 - 559. [Abstract] [Full Text] [PDF]

				A. Gschwendtner, S. Ripke, T. Freilinger, P. Lichtner, B. Muller-Myhsok, H.-E. Wichmann, T. Meitinger, and M. Dichgans Genetic Variation in Soluble Epoxide Hydrolase (EPHX2) Is Associated With an Increased Risk of Ischemic Stroke in White Europeans Stroke, May 1, 2008; 39(5): 1593 - 1596. [Abstract] [Full Text] [PDF]

				J. J. Iliff, L. N. Close, N. R. Selden, and N. J. Alkayed A novel role for P450 eicosanoids in the neurogenic control of cerebral blood flow in the rat Exp Physiol, July 1, 2007; 92(4): 653 - 658. [Abstract] [Full Text] [PDF]

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