Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium

Jia Jia, Catherine Davis, Wenri Zhang, Matthew L. Edin, Sari Jouihan, Taiping Jia, J. Alyce Bradbury, Joan P. Graves, Laura M. DeGraff, Craig R. Lee, Oline Ronnekleiv, Ruikang Wang, Yun Xu, Darryl C. Zeldin, Nabil Alkayed

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. Approach and 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 24 h 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.

Original languageEnglish (US)
Pages (from-to)75-85
Number of pages11
JournalExperimental Neurology
Volume279
DOIs
StatePublished - May 1 2016

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Vascular Endothelium
Protein Isoforms
Cytochrome P-450 Enzyme System
Transgenic Mice
Brain Ischemia
Cytokines
Middle Cerebral Artery Infarction
Reperfusion
Cerebrovascular Circulation
Laser-Doppler Flowmetry
Putamen
Optical Imaging
Arachidonic Acid
Infarction
Blood Vessels
Neuroprotection
Real-Time Polymerase Chain Reaction
Anti-Inflammatory Agents
Ischemia
Endothelial Cells

Keywords

  • Cerebral blood flow
  • Eicosanoids
  • Inflammation
  • Stroke
  • Vasodilation

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium. / Jia, Jia; Davis, Catherine; Zhang, Wenri; Edin, Matthew L.; Jouihan, Sari; Jia, Taiping; Bradbury, J. Alyce; Graves, Joan P.; DeGraff, Laura M.; Lee, Craig R.; Ronnekleiv, Oline; Wang, Ruikang; Xu, Yun; Zeldin, Darryl C.; Alkayed, Nabil.

In: Experimental Neurology, Vol. 279, 01.05.2016, p. 75-85.

Research output: Contribution to journalArticle

Jia, J, Davis, C, Zhang, W, Edin, ML, Jouihan, S, Jia, T, Bradbury, JA, Graves, JP, DeGraff, LM, Lee, CR, Ronnekleiv, O, Wang, R, Xu, Y, Zeldin, DC & Alkayed, N 2016, 'Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium', Experimental Neurology, vol. 279, pp. 75-85. https://doi.org/10.1016/j.expneurol.2016.02.016
Jia, Jia ; Davis, Catherine ; Zhang, Wenri ; Edin, Matthew L. ; Jouihan, Sari ; Jia, Taiping ; Bradbury, J. Alyce ; Graves, Joan P. ; DeGraff, Laura M. ; Lee, Craig R. ; Ronnekleiv, Oline ; Wang, Ruikang ; Xu, Yun ; Zeldin, Darryl C. ; Alkayed, Nabil. / Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium. In: Experimental Neurology. 2016 ; Vol. 279. pp. 75-85.
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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. Approach and 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 24 h 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.",
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T1 - Sex- and isoform-specific mechanism of neuroprotection by transgenic expression of P450 epoxygenase in vascular endothelium

AU - Jia, Jia

AU - Davis, Catherine

AU - Zhang, Wenri

AU - Edin, Matthew L.

AU - Jouihan, Sari

AU - Jia, Taiping

AU - Bradbury, J. Alyce

AU - Graves, Joan P.

AU - DeGraff, Laura M.

AU - Lee, Craig R.

AU - Ronnekleiv, Oline

AU - Wang, Ruikang

AU - Xu, Yun

AU - Zeldin, Darryl C.

AU - Alkayed, Nabil

PY - 2016/5/1

Y1 - 2016/5/1

N2 - 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. Approach and 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 24 h 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.

AB - 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. Approach and 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 24 h 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.

KW - Cerebral blood flow

KW - Eicosanoids

KW - Inflammation

KW - Stroke

KW - Vasodilation

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