Abstract
Disruption of the circadian system caused by disordered exposure to light is pervasive in modern society and increases the risk of cardiovascular disease. The mechanisms by which this happens are largely unknown. ApolipoproteinE-deficient (ApoE−/−) mice are studied commonly to elucidate mechanisms of atherosclerosis. In this study, we determined the effects of light-induced circadian disruption on atherosclerosis in ApoE−/− mice. We first characterized circadian rhythms of behavior, light responsiveness, and molecular timekeeping in tissues from ApoE−/− mice that were indistinguishable from rhythms in ApoE+/+ mice. These data showed that ApoE−/− mice had no inherent circadian disruption and therefore were an appropriate model for our study. We next induced severe disruption of circadian rhythms by exposing ApoE−/− mice to constant light for 12 weeks. Constant light exposure exacerbated atherosclerosis in male, but not female, ApoE−/− mice. Male ApoE−/− mice exposed to constant light had increased serum cholesterol concentrations due to increased VLDL/LDL fractions. Taken together, these data suggest that ApoE−/− mice are an appropriate model for studying light-induced circadian disruption and that exacerbated dyslipidemia may mediate atherosclerotic lesion formation caused by constant light exposure.
Highlights
More than 600,000 people die every year in the U.S from heart disease[1]
Mammalian circadian rhythms are generated by molecular clocks that are located in nearly every tissue in the body[12]
Mice lacking functional Bmal[1], and Clock∆19 mutants, both of which have impaired or arrhythmic circadian clocks, had increased pathological vascular remodeling compared to mice with functional clocks[17]
Summary
More than 600,000 people die every year in the U.S from heart disease[1]. Atherosclerosis, the progressive accumulation of plaques in arteries, is the primary cause of cardiovascular disease (CVD), stroke, and myocardial infarction[2]. PERIOD and CRYPTOCHROME feed back and inhibit the transcription factor activity of BMAL1 and CLOCK, thereby suppressing their own transcription This feedback loop takes approximately 24-hour to complete and generates a 24-hour molecular rhythm. Previous studies in mice have shown that genetic disruption of the circadian molecular timekeeping mechanism causes cardiovascular pathology[15,16,17,18,19]. The ideal mouse model should have normal circadian rhythms and normal responsiveness to light and those rhythms should be susceptible to disruption by perturbation of the light-dark cycle To this end, we first characterized circadian rhythms in ApoE−/− mice. We sought to determine whether circadian disruption with constant light exposure increased atherosclerosis in ApoE−/− mice
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