Carbonyl Reductase 1: a novel regulator of blood pressure in Down Syndrome

Abstract

Background: 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 and 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 potential to impact blood pressure. Methods: Utilising genetically modified mice and telemetric blood pressure measurement, we tested the hypothesis that CBR1 influences blood pressure and that its overexpression contributes to hypotension in DS. Results: In a mouse model of DS (Ts65Dn), which exhibit hypotension, CBR1 activity was increased and pharmacological inhibition of CBR1 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 sympathetic tone and prostaglandin metabolism. Conclusions: 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.