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Mass. General study finds how getting enough sleep reduces cardiovascular disease risk

Sleep-modulating hormone hypocretin found to also control production of inflammatory cells

Massachusetts General Hospital

Getting enough sleep is key to good health, and studies have shown that insufficient sleep increases the risk of serious problems, including cardiovascular disease. Now Massachusetts General Hospital (MGH) investigators have discovered one way that sleep protects against the buildup of arterial plaques called atherosclerosis. In their paper receiving advance online publication in Nature, they describe the mechanism by which insufficient sleep increases production of inflammatory white blood cells known to be major contributors to atherosclerosis.

"We have discovered that sleep helps to regulate the production in the bone marrow of inflammatory cells and the health of blood vessels and that, conversely, sleep disruption breaks down control of inflammatory cell production, leading to more inflammation and more heart disease," says Filip Swirski, PhD, of the MGH Center for Systems Biology, senior author of the Nature paper. "We also have identified how a hormone in the brain known to control wakefulness controls processes in the bone marrow and protects against cardiovascular disease."

To investigate how insufficient sleep increases atherosclerosis, Swirski's team subjected mice genetically programmed to develop atheroslcerosis to repeated interruptions of their sleep, similar to the experience of someone constantly waking up because of noise or discomfort. While there were no changes in weight, cholesterol levels or glucose tolerance in the sleep-deprived mice, compared to animals from the same strain allowed to sleep normally, those subjected to sleep fragmentation developed larger arterial plaques and had higher levels of monocytes and neutrophils - inflammatory cells that contribute to atherosclerosis - in their blood vessels.

Further experiments revealed that the sleep-deprived mice had a nearly two-fold increase in the production in their bone marrow of stem cells that give rise to white blood cells. A hormone called hypocretin, produced in the brain structure called the hypothalamus and known to have a role in the regulation of sleep, was found to play an unexpected role in controlling white blood cell production. While normally produced at high levels when animals - including humans - are awake, hypocretin levels were significantly reduced in the sleep-deprived mice.

The MGH team found that hypocretin regulates production of white blood cells through interaction with neutrophil progenitors in the bone marrow. Neutrophils, they discovered, induce monocyte production through release of a factor called CSF-1, and experiments with mice lacking the gene for hypocretin revealed that the hormone controls CSF-1 expression, monocyte production and the development of arterial plaques. In sleep-deprived animals, the drop in hypocretin led to increased CSF-1 production by neutrophils, elevated monocyte production and accelerated atherosclerosis.

"This is a direct demonstration that hypocretin is also an important inflammatory mediator," says Swirski, an associate professor of Radiology at Harvard Medical School. "We now need to study this pathway in humans, explore additional mechanisms by which proper sleep maintains vascular health and further explore this newly identified neuro-immune axis."

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Cameron McAlpine, PhD, of the MGH Center for Systems Biology is lead author of the Nature paper. The Swirski lab (@SwirskiLab) also collaborated on the study with Máté Kiss, MS, and Christoph Binder, MD, PhD, Medical University of Vienna; Peter Libby, MD, Brigham and Women's Hospital; Anne Vassalli, PhD, and Mehdi Tafti, PhD, University of Lausanne; Thomas Scammell, MD, Beth Israel Deaconess Medical Center, and Matthias Nahrendorf, MD, MGH Radiology. Support for the study includes National Institutes of Health grants R35 HL135752, R01 HL128264 and P01 HL131478 and the American Heart Association Established Investigator Award. Swirski is the Patricia and Scott Eston MGH Research Scholar.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

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