Chronic Circadian Disruption Induces Cardiovascular Disease in Male Mice

Abstract

Circadian rhythm disruption similar to shift work experience increases the risk of cardiometabolic disease. Numerous studies have demonstrated that shift workers have an increased risk of developing hypertension, show decreased endothelial function, and demonstrate an impaired pattern of sodium excretion. Shift work has also been associated with higher incidence of metabolic syndrome. Desynchrony between environmental conditions, such as the light-dark (LD) cycle, and the endogenous circadian clock has detrimental effects in humans and animals. We hypothesized that chronic environmental circadian disruption leads to vascular disease and increased blood pressure. Male 8-week old mice (C57BL/6J) were maintained under a standard light/dark cycle (12 hr light, 12 hr dark, controls) or subjected to a chronic circadian disruption protocol (10 hr light, 10 hr dark), a T20 cycle, with ad libitum access to food and water. Weekly food intake was similar between control mice and mice subjected to a shortened light cycle. Aortic pulse wave velocity (PWV), an index of vascular stiffness, was significantly higher in mice under a T20 cycle for 6 weeks compared to control mice (Control: 1.60±0.1 m/s; T20: 2.25±0.1 m/s; n=6, p=0.0037). Mice subjected to a T20 cycle also showed significantly increased body weight gain after 6 weeks (Control: 1.7±0.3 g; T20: 2.9±0.4 g; n=6, p=0.03). Radiotelemetry revealed blood pressure, heart rate, and locomotor activity diurnal rhythms were disrupted in mice under 10 weeks of a T20 cycle. Control mice showed a significant difference in mean arterial pressure between the inactive and active periods, while this variation was absent in T20 mice (Control 119±3 mm Hg vs. 101±2 mm Hg, active vs. inactive, respectively, p=0.01; T20 115±15 mm Hg vs. 114±11 mm Hg, active vs. inactive, respectively, p=0.92; n=3-4 in all groups). Time of day and the interaction between time of day and light cycle were significant between control and T20 mice (n=3-4, p=0.02 and p=0.04, respectively). In conclusion, these findings demonstrate that chronic circadian disruption leads to vascular stiffness, increased weight gain, and impaired blood pressure rhythm suggesting development of cardiovascular disease and alterations in metabolism.