Dual Oxidase 2 Mediates Cardiovascular, Autonomic, and Baroreflex Function: An in vivo Study in Conscious Mice

Abstract

Changes in circadian rhythm profiles including phase changes and classical dipper/non-dipper profiles have recently been shown to be affected by reactive oxygen species (ROS) in several hypertensive models. Dual oxidase 2 (DUOX2), a new member of the ROS-producing NADPH oxidase family of enzymes, is primarily responsible for the production of thyroid hormone through its generation of hydrogen peroxide. In addition to hypothyroidism, here we report that global knockout of the DUOX2 gene in mice causes both hypotension and bradycardia basally, which are independent of locomotor activity and that which cannot be rescued by thyroid hormone supplementation. Furthermore, DUOX2 knockout mice exhibit a classical 'dipper' profile, which is, at least in part, the result of increased sympathetic control of basal heart rate. Moreover, we report that DUOX2 null mice exhibit an increased baroreflex sensitivity, which was tested by both spontaneous baroreflex analysis and classical vasoactive drug administration. Supplemental real-time PCR and in situ hybridization studies confirm the genotype of DUOX2 null mice and demonstrate that DUOX2 is not expressed in the thyroid of null mice, providing rationale for the low plasma T4 levels observed in DUOX2-/- mice at baseline. In conclusion, we have determined that DUOX2-mediated pathways participate in the regulation of both blood pressure and heart rate and that this occurs via mechanisms independent of thyroid hormone synthesis.