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.
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA; The Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Nelson
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Young
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Rohan N
authors.initials: RN
authors.lastname: Borkar
authors.affiliation: Department of Pathology, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Woltjer
authors.affiliation: Layton Aging and Alzheimer's Disease Center, Department of Neurology, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.affiliation: Layton Aging and Alzheimer's Disease Center, Department of Neurology, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Silbert
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA; Department of Pathology, Oregon Health & Science University, Portland, OR 97239-3098, USA.
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.affiliation: Department of Anesthesiology & Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239-3098, USA; Layton Aging and Alzheimer's Disease Center, Department of Neurology, Oregon Health & Science University, Portland, OR 97239-3098, USA; The Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR 97239-3098, USA. Electronic address: alkayedn@ohsu.edu.
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000367:Age Factors; D000369:Aged, 80 and over; D016009:Chi-Square Distribution; D004247:DNA / Q000737:chemistry / Q000235:genetics; D015140:Dementia, Vascular / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D056784:Leukoencephalopathies / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D004247:DNA; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid
keywords: EETs; EPHX2; Epoxyeicosatrienoic acids; Soluble epoxide hydrolase; Vascular cognitive impairment; White matter hyperintensity