Malbon Alexandra J, Czopek Alicja, Beekman Andrew M, Goddard Zoë R, Boyle Aileen, Ivy Jessica R, Stewart Kevin, Denham Scott G, Simpson Joanna P, Homer Natalie Z, Walker Brian R, Dhaun Neeraj, Bailey Matthew A, Morgan Ruth A
The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, EH25 9RG, U.K.
The Roslin Institute, The University of Edinburgh, Easter Bush Campus, EH25 9RG, U.K.
Biosci Rep. 2025 Feb 26;45(2):157-170. doi: 10.1042/BSR20241636.
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.
每800名儿童中约有1名出生时患有唐氏综合征（DS）这种严重的非整倍体疾病，即21号染色体三体。低血压是与DS相关的常见病症，会对运动耐量和生活质量产生重大影响。对于导致这种低血压表型的因素知之甚少，因此治疗干预措施有限。羰基还原酶1（CBR1）是一种参与前列腺素、糖皮质激素、活性氧和神经递质代谢的酶，由位于21号染色体上的一个基因（CBR1）编码，该基因有可能影响血压。利用转基因小鼠的遥测血压测量技术，我们通过评估体外可能的促成机制，检验了CBR1影响血压及其过表达导致DS低血压的假设。在表现出低血压的DS小鼠模型（Ts65Dn）中，CBR1活性增加，对CBR1的药理抑制导致血压升高。Cbr1杂合缺失的小鼠CBR1酶活性降低，血压升高。进一步的实验表明，潜在机制包括交感神经张力和前列腺素代谢的改变。我们得出结论，CBR1活性有助于血压稳态，抑制CBR1可能为纠正DS的症状性低血压提供一个新的治疗机会。
