Chronic circadian stress raises mean arterial pressure in male, but not female, Bmal1-knockout rats

Abstract

Shiftwork and other forms of circadian disruption are associated with an increased risk of cardiovascular and kidney disease, however, the mechanisms driving these associations have yet to be elucidated. It has been suggested that dyssynchrony between the endogenous molecular clock and the external environment during shiftwork may be connected with the development of cardiorenal pathologies and the dysregulation of blood pressure (BP). Brain and muscle arntl-like protein 1, or Bmal1, is a core component of the molecular clock. Loss of Bmal1 in both male and female rats results in lower BP compared to wild-type (WT) littermate controls. We hypothesized that Bmal1 is necessary for the acclimation to circadian stress induced by chronic circadian stress (CCS). Telemeters were surgically implanted in the abdominal aorta of 12-14 week old rats. After a 2 week recovery, animals were placed in a light-controlled room on a 12:12hr light/dark cycle. After 1 week acclimation, lights were phase-advanced 6hrs every week for 4 weeks. Telemetry data was collected for 2 minutes every 10 minutes each hour at 1000 samples/second and analyzed using cosinor analysis. The MESOR of mean arterial pressure (MAP) was similar pre- and post- CCS in male WT rats (n=8, 107±1 vs. 109±1 mmHg; 2-way ANOVA, p>0.05) and in female WT rats (n=9, 110±1 vs. 112±2 mmHg; p>0.05). Male Bmal1-KO rats (n=9) had higher MAP MESOR after CCS (103±1 vs 108±1mmHg; p<0.05), but female Bmal1-KO rats (n=6) had no change in MAP MESOR after CCS (100±2. vs 100±2 mmHg, p>0.05). MAP amplitude was similar between WT and KO males before- (6.5±0.7 vs. 5.2±0.8 mmHg) and after-CCS (5.1±0.4 vs. 5.3±0.4 mmHg, p>0.05). WT and KO females had similar MAP amplitude before- (7.2±0.6 vs 5.5±0.9 mmHg) and after-CCS (5.7±1.1 vs. 5.6±0.6, p>0.05). In summary, loss of Bmal1 combined with circadian stress resulted in higher BP in a sex- dependent manner. Despite having lower blood pressures pre-CCS, male Bmal1-KO rats had higher MAP after CCS while female Bmal1-KO rats were protected from increased BP. This suggests that Bmal1, a crucial component of the molecular clock, has a sex-specific role in BP regulation and the response to stress. This work is supported by NIH TL1DK139566-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.