Journal
PROSTAGLANDINS & OTHER LIPID MEDIATORS
Volume 113, Issue -, Pages 30-37Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.prostaglandins.2014.09.003
Keywords
Vascular cognitive impairment; Soluble epoxide hydrolase; White matter hyperintensity; EPHX2; Epoxyeicosatrienoic acids; EETs
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Funding
- NIH [R21 AG043857, P30 AG008017]
- Oregon Brain Aging Study (Department of Veterans Affairs) [P30 AG008017, UL1 RR024140]
- NATIONAL CENTER FOR RESEARCH RESOURCES [UL1RR024140] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [T32HL094294] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS044313, R01NS070837] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R21AG043857, P30AG008017] Funding Source: NIH RePORTER
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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. (C) 2014 Elsevier Inc. All rights reserved.
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