Chronic Circadian Misalignment Increases Blood Pressure in Male and Female Bmal1‐KO Rats

Abstract

Circadian misalignment, such as shift work, is an independent risk factor for the development of cardiovascular and renal disease. The molecular clock is ubiquitously expressed in all cell types and nearly 15% of all molecular transcripts are thought to be controlled by the molecular clock. However, it is unknown how environmental stress, such chronic circadian misalignment, can affect blood pressure and if the molecular clock is involved in this response. In this study, we test the hypothesis that chronic circadian misalignment will raise systolic and diastolic blood pressures in rats without a functional molecular clock. Male and female brain-and-muscle ARNTL-like 1 knockout rats (Bmal1-KO) and littermate controls were implanted with a telemetry catheter in the abdominal aorta to record blood pressure rhythms. Rats were allowed to recover from surgery for 10 days in a 12hr:12hr light/dark (LD) cycle. After recovery, animals were placed in the circadian misalignment protocol, wherein lights were phase advanced 6 hours weekly for five weeks. Food and water were available ad libitum for the duration of experiment. Prior to the circadian misalignment protocol, Bmal1KO rats display blood pressures lower than littermate controls with an intact diurnal rhythm. At the end of the protocol, systolic (SBP) and diastolic blood pressures (DBP) were significantly higher in both Bmal1-KO rats and littermate controls of both sexes (3-way ANOVAs, p>0.05 for inactive (7AM to 7PM) and active (7PM to 7AM) period SBP and DBP). Male control animals had an average active period SBP delta of 4.3±3.2 mmHg while male Bmal1-KO animals had an average active period SBP delta of 8.3±1.8 mmHg. Female control animals had an average active period SBP delta of 1.5±1.5 mmHg while female Bmal1-KO rats had an average active period SBP delta of 7.7±8.4 mmHg. This data suggests that circadian misalignment can raise SBP and DBP in rats after only 5 weeks and may provide insight into the mechanisms by which shift work can lead to the development of cardiovascular and renal disease. A functional molecular clock may mitigate the degree of increased blood pressures during circadian misalignment, as Bmal1-KO rats had larger absolute increases in BP after the misalignment protocol. Further studies will address the role of sex and the contribution of specific organs important to the control of BP during circadian misalignment in rats.