Soluble epoxide hydrolase: regulation by estrogen and role in the inflammatory response to cerebral ischemia.
The protection from ischemic brain injury enjoyed by females is linked to the female sex hormone 17beta-estradiol. We tested the hypothesis that neuroprotection by estradiol entails the prevention of ischemia-induced inflammatory response, through suppression of the P450 eicosanoids-metabolizing enzyme soluble epoxide hydrolase (sEH). Ovariectomized female rats with and without estradiol replacement underwent 2-hour middle cerebral artery occlusion (MCAO). SEH expression was determined using Western blot, and inflammatory cytokine mRNA levels were measured at 6, 24 and 48 hours after MCAO. Cytokine mRNA was also measured in sEH-knockout mice, and in rats treated with sEH inhibitors. Estradiol reduced basal and post-ischemic sEH expression. MCAO strongly induced mRNA levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 1beta, which was attenuated in sEH-knockouts, but not by sEH inhibitors. Estradiol replacement exhibited a bimodal effect on cytokine mRNA, with increased early and reduced delayed expression. While estradiol suppresses cerebral sEH expression, and sEH suppression diminishes inflammation after MCAO, our findings suggest that the effect of estrogen on inflammation is complex, and only partially explained by sEH suppression.
Koerner
Ines P
IP
Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Zhang
Wenri
W
Cheng
Jian
J
Parker
Susan
S
Hurn
Patricia D
PD
Alkayed
Nabil J
NJ
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D002536:Cerebral Arteries / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism / Q000502:physiology*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology*; D007249:Inflammation; D008297:Male; D051379:Mice; D008954:Models, Biological; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D004967:Estrogens; D004851:Epoxide Hydrolases