Disturbed sleep and atherosclerosis

This Project Grant award from the National Heart, Lung, and Blood Institute (NHLBI), under the Cardiovascular Diseases Research federal grant program (CFDA 93.837), provides $450,000 in funding to Old Dominion University to investigate the relationship between disturbed sleep and the development of vulnerable atherosclerotic plaques.

The primary objectives are to: 1) examine the role of NADPH-dependent oxidative stress in accelerating the formation of vulnerable atherosclerotic plaques in response to sleep fragmentation, and 2) assess whether restoring sleep quality can improve the phenotype of existing atherosclerotic plaques and reduce atherogenesis. The research will utilize mouse models to study the impact of sleep disturbances on gut-associated inflammation, oxidative stress, and neutrophil activation, and how these factors contribute to the progression of vulnerable atherosclerotic lesions. The findings from this 3-year project could lead to the development of new treatments aimed at preventing sleep-related cardiovascular disease.

Abstract

Atherosclerosis is the major etiological process responsible for 25% of global deaths. Numerous reports indicate both the adaptive and innate immune systems are involved in atherogenesis. In addition to well- established risk factors such as age, hypertension, high circulating levels of low-density lipoprotein cholesterol, and type 2 diabetes, the quality and quantity of sleep are now recognized as important factors for atherogenesis. Sleep is vital for life. In the USA, ~70 million people report insufficient sleep and/or fragmented sleep due to work responsibilities, sleep apnea, caregiving, and lifestyle choices. Changes in sleep are a part of the normal aging process, leading to increased sleep fragmentation (SF), nighttime awakenings, and a greater tendency for daytime sleep. Dysregulation of normal sleep negatively affects homeostatic functions and is associated with an increased risk of chronic diseases, including atherosclerosis. Long-term SF may lead to endothelial dysfunction, oxidative stress, and altered vessel wall structure. SF has a negative impact on atherogenesis through the regulation of myelopoiesis, highlighting the complex relationship between sleep, the vascular system, and the immune system. One of the remaining outstanding questions in the field is the extent to which SF affects the vulnerability of plaques. Another important question that remains to be investigated is whether the restoration of sleep quality might reduce atherosclerosis development and improve the phenotype of the plaques. Our results indicate that SF supports neutrophil functions such as ROS and net production. We detect increased circulating levels of LPS that might serve as a neutrophil activator during SF. Competitive homing experiments clearly demonstrated that SF directs neutrophil recruitment into the aorta. Importantly, neutrophil depletion improves plaque phenotype of SF mice. One of the strongest phenotypes observed in the circulation and the GUT was a significant degree of oxidative stress, cell death, and neutrophil activation. GUT inflammation was also supported by alterations in the intestinal immune composition. In this application, we propose the hypothesis that disturbed sleep negatively influences GUT-associated inflammation, triggering LPS-induced oxidative stress, and activating neutrophils, which, in turn, plays a key role in the formation of accelerated vulnerable plaques. Here, we propose to investigate the role of nadph-dependent oxidative stress in vulnerable atherosclerotic plaque formation in response to SF in HFD-FED via neutrophil or intestinal epithelial cell-specific nadph-deficient apoe-/- mice (aim 1). In aim 2, we will test to what extent restoring sleep quality would improve the phenotype of atherosclerotic plaques and reduce atherogenesis. The findings from this proposal could lead to the development of new treatments aimed at preventing GUT-associated and neutrophil- induced oxidative stress and suppressing accelerated atherogenesis induced by SF.