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.
authors.affiliation: Department of Neurology, Huashan Hospital of Fudan University, Shanghai, People's Republic of China.|Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 720 Rutland Ave, Traylor 809, Baltimore, MD, 21205, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.affiliation: Department of Pharmacology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Roman
authors.affiliation: Department of Physiology, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA.|Clement J. Zablocki VA Medical Center, Milwaukee, WI, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Harder
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 720 Rutland Ave, Traylor 809, Baltimore, MD, 21205, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 720 Rutland Ave, Traylor 809, Baltimore, MD, 21205, USA. zyang4@jhmi.edu.
authors.forename: Zeng-Jin
authors.identifier: http://orcid.org/0000-0001-8187-8656
authors.initials: ZJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005947:Glucose / Q000172:deficiency*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D020033:Protein Isoforms / Q000096:biosynthesis; D015854:Up-Regulation / Q000502:physiology
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D020033:Protein Isoforms; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D005947:Glucose; D010100:Oxygen
keywords: 20-HETE; Cytochrome P450; Eicosanoid; Ischemia; Oxygen–glucose deprivation