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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Approximately one in every 800 children is born with the severe aneuploid condition of Down syndrome (DS), a trisomy of chromosome 21. Low blood pressure (hypotension) is a common condition associated with DS and can have a significant impact on exercise tolerance and quality of life. Little is known about the factors driving this hypotensive phenotype, therefore therapeutic interventions are limited. Carbonyl reductase 1 (CBR1) is an enzyme contributing to the metabolism of prostaglandins, glucocorticoids, reactive oxygen species and neurotransmitters, encoded by a gene (CBR1) positioned on chromosome 21 with the potential to affect blood pressure. Utilising telemetric blood pressure measurement of genetically modified mice, we tested the hypothesis that CBR1 influences blood pressure and that its overexpression contributes to hypotension in DS by evaluating possible contributing mechanisms in vitro. In a mouse model of DS (Ts65Dn), which exhibits hypotension, CBR1 activity was increased and pharmacological inhibition of CBR1 ed to increased blood pressure. Mice heterozygous null for Cbr1 had reduced CBR1 enzyme activity and elevated blood pressure. Further experiments indicate that the underlying mechanisms include alterations in both sympathetic tone and prostaglandin metabolism. We conclude that CBR1 activity contributes to blood pressure homeostasis and inhibition of CBR1 may present a novel therapeutic opportunity to correct symptomatic hypotension in DS.
Author(s): Malbon AJ, Czopek A, Beekman AM, Goddard ZR, Boyle A, Ivy JR, Stewart K, Walker BR, Dhaun N, Bailey MA, Morgan RA
Publication type: Article
Publication status: Published
Journal: Bioscience Reports
Year: 2025
Volume: 45
Issue: 2
Print publication date: 26/02/2025
Online publication date: 27/01/2025
Acceptance date: 23/01/2025
Date deposited: 24/01/2025
ISSN (print): 0144-8463
ISSN (electronic): 1573-4935
Publisher: Portland Press Ltd.
URL: https://doi.org/10.1042/BSR20241636
DOI: 10.1042/BSR20241636
Data Access Statement: The data included in this study are available from the corresponding authors upon reasonable request.
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