title: Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium.
abstract: OBJECTIVE
  Cytochrome P450 epoxygenases (CYP) metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), which exhibit vasodilatory, anti-inflammatory and neuroprotective actions in experimental cerebral ischemia. We evaluated the effect of endothelial-specific CYP overexpression on cerebral blood flow, inflammatory cytokine expression and tissue infarction after focal cerebral ischemia in transgenic mice.
  
  
  RESULTS
  Male and female wild-type and transgenic mice overexpressing either human CYP2J2 or CYP2C8 epoxygenases in vascular endothelium under control of the Tie2 promoter (Tie2-CYP2J2 and Tie2-CYP2C8) were subjected to 60-min middle cerebral artery occlusion (MCAO). Microvascular cortical perfusion was monitored during vascular occlusion and reperfusion using laser-Doppler flowmetry and optical imaging. Infarct size and inflammatory cytokines were measured at 24h of reperfusion by TTC and real-time quantitative PCR, respectively. Infarct size was significantly reduced in both Tie2-CYP2J2 and Tie2-CYP2C8 transgenic male mice compared to corresponding WT male mice (n=10 per group, p<0.05). Tie2-CYP2J2, but not Tie2-CYP2C8 male mice maintained higher blood flow during MCAO; however, both Tie2-CYP2J2 and Tie2-CYP2C8 had lower inflammatory cytokine expression after ischemia compared to corresponding WT males (n=10 per group for CBF and n=3 for cytokines, p<0.05). In females, a reduction in infarct was observed in the caudate-putamen, but not in the cortex or hemisphere as a whole and no differences were observed in blood flow between female transgenic and WT mice (n=10 per group).
  
  
  CONCLUSIONS
  Overexpression of CYP epoxygenases in vascular endothelial cells protects against experimental cerebral ischemia in male mice. The mechanism of protection is in part linked to enhanced blood flow and suppression of inflammation, and is both sex- and CYP isoform-specific.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, The Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Davis
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, The Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Wenri
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, The Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA.
authors.forename: Sari
authors.initials: S
authors.lastname: Jouihan
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, USA.
authors.forename: Taiping
authors.initials: T
authors.lastname: Jia
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: J Alyce
authors.initials: JA
authors.lastname: Bradbury
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Joan P
authors.initials: JP
authors.lastname: Graves
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, USA.
authors.forename: Oline
authors.initials: O
authors.lastname: Ronnekleiv
authors.affiliation: Department of Biomedical Engineering, University of Washington, Seattle, WA, USA.
authors.forename: Ruikang
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Nanjing School of Medicine, Nanjing, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, The Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, USA. Electronic address: alkayedn@ohsu.edu.
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002421:Caudate Nucleus / Q000473:pathology; D002533:Cerebral Angiography; D002560:Cerebrovascular Circulation; D065727:Cytochrome P-450 CYP2C8 / Q000096:biosynthesis / Q000235:genetics; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000201:enzymology*; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000066829:Neuroprotection; D011699:Putamen / Q000473:pathology; D012727:Sex Characteristics
chemical_list: C000717350:CYP2J2 protein, human; D016207:Cytokines; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D000090762:Cytochrome P-450 CYP2J2
keywords: Cerebral blood flow; Eicosanoids; Inflammation; Stroke; Vasodilation