Summary Sleep restriction is associated with increased cardiovascular risk, which is more pronounced in women than in men. Recently, we reported the first causal evidence that mild, prolonged sleep restriction that mimics “real-life” conditions impairs endothelial function , a key step in the development and progression of cardiovascular disease, in healthy women. However, the underlying mechanisms are unclear. In model organisms, sleep restriction increases oxidative stress and positively regulates the antioxidant response through the induction of nuclear antioxidant regulatory factor (erythroid derivative 2)-like 2 (Nrf2). Here, we directly assessed endothelial cell oxidative stress and antioxidant responses in healthy women (n = 35) after 6 weeks of mild sleep restriction (1.5 h less than usual sleep) using a randomized crossover design. Sleep restriction markedly increased endothelial oxidative stress without upregulating the antioxidant response. Using RNA-seq and a predicted protein-protein interaction database, we identified reduced expression of the endothelial defect in Cullin Neddylation-1 domain containing 3 (DCUN1D3), a protein that licenses Nrf2 antioxidant responses, as a mediator of altered endothelial antioxidant response during sleep restriction. Therefore, sleep restriction impairs the elimination of endothelial oxidative stress that over time increases cardiovascular risk. |
Figure : Endothelial cell function during wakefulness is impaired after sleep restriction compared to adequate sleep. After adequate sleep, endothelial oxidative stress that accumulates during wakefulness is eliminated by an adequate antioxidant response. SRF mRNA expression increases after increased sleep pressure during wakefulness, upregulating DCUN1D3 and sequestering Cul3 to the plasma membrane. Reduced availability of Cul3 in the Nrf2 ubiquitination complex releases Nrf2 and allows its nuclear translocation and activation of antioxidant genes. Following sleep restriction, endothelial antioxidant responses are not adequately regulated, leading to increased endothelial oxidative stress. Reduction of SRF mRNA expression during wakefulness after sleep restriction leads to a reduction in DCUN1D3 expression and consequent increase in the availability of Cul3 in the Nrf2 ubiquitination complex, which traps Nrf2 and prevents its nuclear translocation and the activation of antioxidant genes. Impaired endothelial antioxidant response after insufficient sleep causes increased oxidative stress during wakefulness, which impairs endothelial function and may increase cardiovascular risk.
Test record: NCT02835261
Comments
Haven’t you gotten enough sleep? Your vascular cells are drowning in oxidants.
Many Americans (about a third) routinely sleep only five to six hours instead of the recommended seven to eight hours. But even a mild, chronic sleep deficit can increase the risk of developing heart disease later in life: Surveys of thousands of people have found that people who report mild but chronic sleep deficits have more heart disease later in life than those who report mild but chronic sleep deficits. people who get enough sleep.
A new Columbia study of women shows what happens in the body during mild and chronic sleep deprivation.
After just six weeks of reduced sleep , the study found, the cells lining our blood vessels are flooded with harmful oxidants . And unlike well-rested cells, sleep-restricted cells fail to activate antioxidant responses to eliminate destructive molecules.
The result: inflamed and dysfunctional cells, an early step in the development of cardiovascular diseases.
"This is one of the first direct evidence showing that mild, chronic sleep deficits cause heart disease," says study leader Sanja Jelic, MD, director of the Columbia Sleep Medicine Center and professor of medicine at the Division of Pulmonary, Allergies and Heart Diseases. and Critical Care Medicine at Columbia University Vagelos College of Physicians and Surgeons.
"So far we have only seen associations between sleep and heart health in epidemiological studies, but these studies could be contaminated by many confounding factors that cannot be identified or adjusted for. Only randomized controlled studies can determine whether this connection is real and "What changes in the body caused by short sleep could increase heart disease."
Previous studies did not examine chronic sleep deficits. Studies on human sleep have examined the physiological effects of a few nights of deep sleep deprivation.
"But that’s not how people behave night after night. Most people get up at about the same time every day, but they tend to push their bedtime back an hour or two," says Jelic. "We wanted to mimic that behavior, which is the most common sleep pattern we see in adults."
Researchers screened nearly 1,000 women in Washington Heights for the study, enrolling 35 healthy women who typically sleep seven to eight hours each night and who could complete the 12-week study.
For six weeks the women slept according to their usual routine; During the other six weeks they went to bed 1.5 hours later than usual. Each participant’s sleep was checked with wrist-worn sleep trackers.
Bottom line: just go to sleep
"Many problems could be solved if people slept at least seven to eight hours a night," says Jelic. "Young, healthy people should know that if they continue to sleep fewer hours, they are aggravating their cardiovascular risk."
Next steps
Recent epidemiological studies suggest that inconsistent bedtimes may increase the risk of heart disease. Jelic’s team is designing a study to see whether bedtime variability affects vascular cells in the same way as short, chronic but regular sleep.
