Role of soluble epoxide hydrolase in age-related vascular cognitive decline

Jonathan W. Nelson; Jennifer M. Young; Rohan N. Borkar; Randy L. Woltjer; Joseph F. Quinn; Lisa C. Silbert; Marjorie R. Grafe; Nabil J. Alkayed

doi:10.1016/j.prostaglandins.2014.09.003

Role of soluble epoxide hydrolase in age-related vascular cognitive decline

Jonathan W. Nelson
, Jennifer M. Young
, Rohan N. Borkar
, Randy L. Woltjer
, Joseph F. Quinn
, Lisa C. Silbert
, Marjorie R. Grafe
, Nabil J. Alkayed

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15-dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI.

Original language	English (US)
Pages (from-to)	30-37
Number of pages	8
Journal	Prostaglandins and Other Lipid Mediators
Volume	113-115
DOIs	https://doi.org/10.1016/j.prostaglandins.2014.09.003
State	Published - Sep 30 2014

Funding

This work was supported by funds from the NIH grant R21 AG043857 (NJA) and P30 AG008017 . We would also like to thank the Oregon Brain Aging Study (OBAS; PI: Kaye; supported by Department of Veterans Affairs , P30 AG008017 , UL1 RR024140 ) and the Oregon Alzheimer Disease Center (Director: Kaye; P30 AG008017) for providing access to control and VCI samples and data. Additionally, we would like to acknowledge the University Shared Resource Program and the BSR/PKCore for the assistance with the eicosanoid quantification. We also wish to acknowledge Stefanie Kaech-Petrie and the Advanced Light Microscopy Core at The Jungers Center for technical assistance with fluorescence image acquisition. Finally, we would like to thank all of the research participates who made this study possible.

Funders	Funder number
Oregon Alzheimer Disease Center
Oregon Brain Aging Study
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	R21 AG043857
National Institute of Aging	P30AG008017
U.S. Department of Veterans Affairs	UL1 RR024140

Keywords

EETs
EPHX2
Epoxyeicosatrienoic acids
Soluble epoxide hydrolase
Vascular cognitive impairment
White matter hyperintensity

ASJC Scopus subject areas

Biochemistry
Physiology
Pharmacology
Cell Biology

Access to Document

10.1016/j.prostaglandins.2014.09.003

Cite this

@article{6428ab57cd8449c2b2e80d58c16c9756,

title = "Role of soluble epoxide hydrolase in age-related vascular cognitive decline",

abstract = "P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15-dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI.",

keywords = "EETs, EPHX2, Epoxyeicosatrienoic acids, Soluble epoxide hydrolase, Vascular cognitive impairment, White matter hyperintensity",

author = "Nelson, \{Jonathan W.\} and Young, \{Jennifer M.\} and Borkar, \{Rohan N.\} and Woltjer, \{Randy L.\} and Quinn, \{Joseph F.\} and Silbert, \{Lisa C.\} and Grafe, \{Marjorie R.\} and Alkayed, \{Nabil J.\}",

year = "2014",

month = sep,

day = "30",

doi = "10.1016/j.prostaglandins.2014.09.003",

language = "English (US)",

volume = "113-115",

pages = "30--37",

journal = "Prostaglandins and Other Lipid Mediators",

issn = "1098-8823",

publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Role of soluble epoxide hydrolase in age-related vascular cognitive decline

AU - Nelson, Jonathan W.

AU - Young, Jennifer M.

AU - Borkar, Rohan N.

AU - Woltjer, Randy L.

AU - Quinn, Joseph F.

AU - Silbert, Lisa C.

AU - Grafe, Marjorie R.

AU - Alkayed, Nabil J.

PY - 2014/9/30

Y1 - 2014/9/30

N2 - P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15-dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI.

AB - P450 eicosanoids are important regulators of the cerebral microcirculation, but their role in cerebral small vessel disease is unclear. We tested the hypothesis that vascular cognitive impairment (VCI) is linked to reduced cerebral microvascular eicosanoid signaling. We analyzed human brain tissue from individuals formerly enrolled in the Oregon Brain Aging Study, who had a history of cognitive impairment histopathological evidence of microvascular disease. VCI subjects had significantly higher lesion burden both on premortem MRI and postmortem histopathology compared to age- and sex-matched controls. Mass spectrometry-based eicosanoid analysis revealed that 14,15-dihydroxyeicosatrienoic acid (DHET) was elevated in cortical brain tissue from VCI subjects. Immunoreactivity of soluble epoxide hydrolase (sEH), the enzyme responsible for 14,15-DHET formation, was localized to cerebral microvascular endothelium, and was enhanced in microvessels of affected tissue. Finally, we evaluated the genotype frequency of two functional single nucleotide polymorphisms of sEH gene EPHX2 in VCI and control groups. Our findings support a role for sEH and a potential benefit from sEH inhibitors in age-related VCI.

KW - EETs

KW - EPHX2

KW - Epoxyeicosatrienoic acids

KW - Soluble epoxide hydrolase

KW - Vascular cognitive impairment

KW - White matter hyperintensity

UR - https://www.scopus.com/pages/publications/84910018436

UR - https://www.scopus.com/pages/publications/84910018436#tab=citedBy

U2 - 10.1016/j.prostaglandins.2014.09.003

DO - 10.1016/j.prostaglandins.2014.09.003

M3 - Article

C2 - 25277097

AN - SCOPUS:84910018436

SN - 1098-8823

VL - 113-115

SP - 30

EP - 37

JO - Prostaglandins and Other Lipid Mediators

JF - Prostaglandins and Other Lipid Mediators

ER -

Role of soluble epoxide hydrolase in age-related vascular cognitive decline

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this