PMID- 17460077
OWN - NLM
STAT- MEDLINE
DCOM- 20070515
LR  - 20200225
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 27
IP  - 17
DP  - 2007 Apr 25
TI  - Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to 
      neuronal survival after ischemic injury.
PG  - 4642-9
AB  - 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.
FAU - Koerner, Ines P
AU  - Koerner IP
AD  - Department of Anesthesiology and Peri-Operative Medicine, Oregon Health & Science 
      University, Portland, Oregon 97239-3098, USA.
FAU - Jacks, Rachel
AU  - Jacks R
FAU - DeBarber, Andrea E
AU  - DeBarber AE
FAU - Koop, Dennis
AU  - Koop D
FAU - Mao, Peizhong
AU  - Mao P
FAU - Grant, David F
AU  - Grant DF
FAU - Alkayed, Nabil J
AU  - Alkayed NJ
LA  - eng
GR  - R01 NS044313/NS/NINDS NIH HHS/United States
GR  - NS049210/NS/NINDS NIH HHS/United States
GR  - NS44313/NS/NINDS NIH HHS/United States
GR  - ES011630/ES/NIEHS NIH HHS/United States
GR  - GM56708/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Vasodilator Agents)
RN  - 81276-03-1 (14,15-epoxy-5,8,11-eicosatrienoic acid)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - EC 3.3.2.10 (EPHX2 protein, human)
RN  - FC398RK06S (8,11,14-Eicosatrienoic Acid)
SB  - IM
MH  - 8,11,14-Eicosatrienoic Acid/analogs & derivatives/pharmacology
MH  - Animals
MH  - Brain Ischemia/metabolism/pathology/*physiopathology
MH  - Cell Death/drug effects/physiology
MH  - Cell Survival/drug effects/physiology
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology
MH  - Epoxide Hydrolases/*genetics/metabolism
MH  - Female
MH  - Gene Expression Regulation, Enzymologic
MH  - Humans
MH  - Neurons/*cytology/*enzymology
MH  - *Polymorphism, Genetic
MH  - Pregnancy
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Solubility
MH  - Stroke/metabolism/pathology/physiopathology
MH  - Transduction, Genetic
MH  - Vasodilator Agents/pharmacology
PMC - PMC6672984
EDAT- 2007/04/27 09:00
MHDA- 2007/05/16 09:00
PMCR- 2007/10/25
CRDT- 2007/04/27 09:00
PHST- 2007/04/27 09:00 [pubmed]
PHST- 2007/05/16 09:00 [medline]
PHST- 2007/04/27 09:00 [entrez]
PHST- 2007/10/25 00:00 [pmc-release]
AID - 27/17/4642 [pii]
AID - 3213564 [pii]
AID - 10.1523/JNEUROSCI.0056-07.2007 [doi]
PST - ppublish
SO  - J Neurosci. 2007 Apr 25;27(17):4642-9. doi: 10.1523/JNEUROSCI.0056-07.2007.