Light‐Dark Patterns Mirroring Shift Work Accelerate Atherosclerosis and Promote Vulnerable Lesion Phenotypes

BACKGROUND: Despite compelling epidemiological evidence that circadian disruption inherent to long‐term shift work enhances atherosclerosis progression and vascular events, the underlying mechanisms remain poorly understood. A challenge to the use of mouse models for mechanistic and interventional studies involving light‐dark patterns is that the spectral and absolute sensitivities of the murine and human circadian systems are very different, and light stimuli in nocturnal mice should be scaled to represent the sensitivities of the human circadian system. METHODS AND RESULTS: We used calibrated devices to deliver to low‐density lipoprotein receptor knockout mice light‐dark patterns representative of that experienced by humans working day shifts or rotating shift schedules. Mice under day shifts were maintained under regular 12 hours of light and 12 hours of dark cycles. Mice under rotating shift schedules were subjected for 11 weeks to reversed light‐dark patterns 4 days in a row per week, followed by 3 days of regular light‐dark patterns. In both protocols the light phases consisted of monochromatic green light at an irradiance of 4 µW/cm(2). We found that the shift work paradigm disrupts the foam cell's molecular clock and increases endoplasmic reticulum stress and apoptosis. Lesions of mice under rotating shift schedules were larger and contained less prostabilizing fibrillar collagen and significantly increased areas of necrosis. CONCLUSIONS: Low‐density lipoprotein receptor knockout mice under light‐dark patterns analogous to that experienced by rotating shift workers develop larger and more vulnerable plaques and may represent a valuable model for further mechanistic and/or interventional studies against the deleterious vascular effects of rotating shift work.