Chronic circadian disruption in cardiovascular disease

Night shift workers have an increased risk of both cardiovascular and metabolic disease. Night shift work is associated with a shift in light exposure and food intake to the normally inactive phase, leading to disruption of the hormonal and metabolic flux. Data in humans and animals shows the loss of circadian rhythms leads to cardiometabolic disease. Recent studies have demonstrated beneficial effects of intermittent fasting or time-restricted feeding on cardiometabolic health in humans and animals. There is a gap in our knowledge of whether the lifestyle intervention, 12-h feeding-fasting, time-restricted feeding schedule (TRF-12), will reverse chronic circadian disruption-mediated cardiometabolic disease. Loss of Bmal1, a critical circadian clock gene, results in vascular dysfunction and abolishes day-night rhythmicity in locomotor activity and cardiovascular rhythms. Reversal of the light-dark cycle as well as in feeding-fasting cycle leads to impairments in both central and peripheral circadian clock function. Our data show that mice exposed to TRF-12 display increased locomotor activity and enhanced day/night difference in heart rate. Further, mice under chronic circadian disruption (10-h light:10-h dark cycle) display higher aortic pulse wave velocity, indicating vascular stiffness, with disrupted blood pressure, heart rate, and activity rhythms. AMP kinase is an important regulator of metabolism and also serves as a regulator of circadian clock function. Our data show that vascular AMPK activation is diurnally regulated, and inhibiting AMPK activation slows the aorta circadian clock gene rhythm, suggesting vascular AMPK activation is important for circadian rhythms in vascular function. Our data show that mice under chronic circadian disruption show increased body weight gain without a change in food intake. The overall goal of this Career Development Award proposal is to provide mechanistic insight into whether aTRF will alleviate vascular disease mediated by circadian disruption. Two aims are designed to investigate this overall goal: Aim 1: To test the hypothesis that TRF-12 will resynchronize central (SCN) and peripheral (vascular) clock function to abolish circadian disruption-induced vascular disease. Aim 2: To test the hypothesis that TRF-12 will activate vascular AMP kinase to abrogate chronic circadian disruption-induced vascular disease.