Soluble epoxide hydrolase: sex differences and role in endothelial cell survival.
OBJECTIVE
Sex differences in cerebral ischemic injury are, in part, attributable to the differences in cerebrovascular perfusion. We determined whether the brain microvascular endothelial cells (ECs) isolated from the female brain are more resistant to ischemic injury compared with male ECs, and whether the difference is attributable to lower expression of soluble epoxide hydrolase and higher levels of vasoprotective epoxyeicosatrienoic acids (EETs). We also determined whether protection by EETs is linked to the inhibition of rho-kinase (ROCK).


RESULTS
EC ischemic damage was measured after oxygen-glucose deprivation (OGD) using propidium iodide (PI) and cleaved caspase-3 labeling. Expression of soluble epoxide hydrolase was determined by quantitative polymerase chain reaction and immunocytochemistry, EETs levels by liquid chromatography-tandem mass spectrometry, and ROCK activity by ELISA. EC damage was higher in males compared with females, which correlated with higher soluble epoxide hydrolase mRNA, stronger immunoreactivity, and lower EETs compared with female ECs. Inhibition of soluble epoxide hydrolase abolished the sex difference in EC damage. ROCK activity was higher in male versus female ECs after OGD, and sex differences in EC damage and ROCK activity were abolished by 14,15-EET and ROCK inhibition.


CONCLUSIONS
Sex differences in ischemic brain injury are, in part, attributable to differences in EET-mediated inhibition of EC ROCK activation after ischemia.
Division of Cardiovascular Medicine, Oregon Health & Science University, 3181 S.W. Sam Jackson Pk. Rd, Portland, OR 97239-3098, USA.
Nandita C
NC
Gupta
Catherine M
CM
Davis
Jonathan W
JW
Nelson
Jennifer M
JM
Young
Nabil J
NJ
Alkayed
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000209:etiology*; D002470:Cell Survival; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D004851:Epoxide Hydrolases / Q000032:analysis / Q000276:immunology / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011725:Pyridines / Q000494:pharmacology; D012727:Sex Characteristics; D012995:Solubility; D054460:rho-Associated Kinases / Q000378:metabolism
D000577:Amides; D011725:Pyridines; C108830:Y 27632; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D054460:rho-Associated Kinases; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid