@article{b8ad7828754e491298728e9ebe47c8a6,
title = "Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen–Glucose Deprivation in Cortical Neurons",
abstract = "20-Hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictor, is a cytochrome P450 (CYP) 4A/4F-derived metabolite of arachidonic acid. Inhibition of 20-HETE synthesis protects brain from ischemic injury. However, that protection is not associated with changes in cerebral blood flow. The present study examined whether CYP4A isoforms are expressed in neurons, whether they produce 20-HETE in neurons, and whether neuronally derived 20-HETE exerts direct neurotoxicity after oxygen–glucose deprivation (OGD). The expression of Cyp4a10 and Cyp4a12a mRNA in cultured mouse cortical neurons increased significantly at 1 and 3 h after exposure to 1 h of OGD. Reoxygenation also markedly augmented the expression of CYP4A protein in neurons and increased 20-HETE levels in the culture medium. Cell viability after OGD increased after treatment with a 20-HETE synthesis inhibitor or an antagonist. That effect was reversed by co-administration of a 20-HETE agonist. These results indicate that neurons express Cyp4a10 and 4a12a, that expression of these isoforms is upregulated by OGD stress, and that neuronally derived 20-HETE directly contributes to neuronal death after reoxygenation.",
keywords = "20-HETE, Cytochrome P450, Eicosanoid, Ischemia, Oxygen–glucose deprivation",
author = "Hui Zhang and Falck, {J R} and Roman, {Richard J.} and Harder, {David R.} and Koehler, {Raymond C.} and Yang, {Zeng Jin}",
note = "Funding Information: by a grant from the Veterans Administration Research Career Scientist Award. R.C.K was supported by NIH Grants NS060703 and NS067525. Z.J.Y. was supported by American Heart Association Grant 13BGIA16850043 and Stimulating and Advancing ACCM Research (StAAR) grant from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine. Funding Information: Acknowledgements H.Z. was supported by a Chinese Scholarship Council student fellowship grant. J.R.F. was supported by National Institutes of Health (NIH) Grants HL111392, DK38226, and HL034300 and by the Robert A. Welch Foundation (I-0011). R.J.R. was supported by NIH Grants HL36279 and DK104184. D.R.H. was supported by NIH Grants HL033833, HL092105, and HL105997 and Funding Information: H.Z. was supported by a Chinese Scholarship Council student fellowship grant. J.R.F. was supported by National Institutes of Health (NIH) Grants HL111392, DK38226, and HL034300 and by the Robert A. Welch Foundation (I-0011). R.J.R. was supported by NIH Grants HL36279 and DK104184. D.R.H. was supported by NIH Grants HL033833, HL092105, and HL105997 and by a grant from the Veterans Administration Research Career Scientist Award. R.C.K was supported by NIH Grants NS060703 and NS067525. Z.J.Y. was supported by American Heart Association Grant 13BGIA16850043 and Stimulating and Advancing ACCM Research (StAAR) grant from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine. H.Z., R.J.R., and Z.-J.Y. performed the experiments. R.C.K and Z.-J.Y. conceived and designed the experiments and analyzed the data. J.R.F. provided 20-HETE agonist and antagonist. J.R.F., R.J.R., and D.R. H. provided oversight for the project. R.C.K. and Z.-J.Y. compiled the manuscript and figure preparation. The authors declare that they have no conflicts of interest. Publisher Copyright: {\textcopyright} 2017, Springer Science+Business Media New York.",
year = "2017",
month = oct,
day = "1",
doi = "10.1007/s10571-017-0462-8",
language = "English (US)",
volume = "37",
pages = "1279--1286",
journal = "Cellular and Molecular Neurobiology",
issn = "0272-4340",
publisher = "Springer New York",
number = "7",
}