2017 Cardiovascular Research Day Abstract Book

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Circadian disruption and atherosclerosis in ApolipoproteinE-deficient mice
Eric McGann 1 • Jeffery Chalfant, MS 1 • Deborah Howatt 2 • Julie Pendergast, PhD 1
1Biology, University of Kentucky • 2 Saha Cardiovascular Research Center, University of Kentucky
Staff
The circadian system is a network of molecular clocks located throughout the body. These clocks
coordinate daily rhythms of behavior and physiology with environmental cycles. Shift work, which
chronically disrupts circadian rhythms, increases the risk of developing cardiovascular diseases.
The mechanisms by which this happens, however, are largely unknown. Our long-term goal is to
determine how disruption of circadian rhythms causes cardiovascular disease. Atherosclerosis is
the build-up of plaques in arteries and can lead to myocardial infarction and stroke. In this study,
we sought to investigate whether circadian disruption accelerates atherosclerosis in mice. Wildtype
mice do not develop atherosclerotic lesions. Therefore, we studied C57BL/6J ApolipoproteinEdeficient
(ApoE-/-) mice because they spontaneously develop atherosclerotic lesions. We first
characterized circadian rhythms in ApoE-/- mice. We found that circadian behavioral rhythms,
including free-running periods of activity in constant darkness and constant light, phase angles of
entrainment, and phase shifts to light pulses, were similar between wild-type and ApoE-/- mice.
These data show that ApoE-/- mice had no deficits in their circadian behavior rhythms or light
responsiveness. Next, we determined if molecular circadian rhythms in tissues were altered in
ApoE-/- mice. We analyzed the expression of the circadian timekeeping protein, PERIOD2, in
central and peripheral tissues using a luciferase reporter. We found that PERIOD2::LUCIFERASE
rhythms in tissues were similar in wild-type and ApoE-/- mice. We next determined the effect of
constant light on the development of atherosclerosis in ApoE-/- mice. After 3 months in constant
light, locomotor activity was arrhythmic or the rhythm was severely disrupted. In addition,
atherosclerotic lesion area was increased in ApoE-/- mice in constant light compared to those in
control 12h light-12h dark condition. Together, these data demonstrate that ApoE-/- mice have
normal circadian rhythms and chronic circadian disruption accelerates atherosclerosis in ApoE-/-
mice.
This study was funded by National Institutes of Health grant P20GM103527, the Gertude F. Ribble
Trust, and the University of Kentucky.
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