0010 Circadian dysregulation of the cardiopulmonary system in a mouse model of obstructive sleep apnea

Abstract Introduction Intermittent hypoxia (IH) is a condition that occurs in people with obstructive sleep apnea (OSA), in which breathing is repeatedly interrupted during sleep. This can cause a lack of oxygen (hypoxia) in the body. OSA is associated with chronic systemic inflammation, thought to increase the risk of comorbid conditions, including cardiovascular disease. However, the mechanisms behind these pathologic consequences are not well understood. We hypothesize that IH dysregulates the circadian system and heightens inflammatory responses through hypoxia-inducible factors (HIFs), contributing to the end organ damage among patients with OSA. Here, we tested this hypothesis using a mouse model of OSA. Methods C57BL/6J background mice were exposed to normoxic or IH conditions for either seven days (short-term) or six weeks (long-term) under 12-hour light and 12-hour dark cycles. After exposure, cardiopulmonary tissues were collected and processed to evaluate circadian transcriptomes, including among HIFs. We also measured protein levels of inflammatory mediators in the heart and lung to compare the effects of short- and long-term exposure to IH. In addition, we measured the real-time circadian physiology of blood pressure, heart rate, activity, and core body temperature using a DSI-telemetry system. Results We observed dysregulated circadian systems of the lung and heart following IH exposure. IH also had a negative impact on immune responses in the heart and lung tissue, resulting in a decrease in inflammatory mediators following short-term exposure. However, long-term exposure to IH had the opposite effect, causing an overall increase in inflammatory mediators that contribute to comorbid cardiopulmonary pathologies. In addition, we also observed altered circadian physiology, particularly a significant increase in core body temperature. Conclusion Our results suggest that a dysregulated circadian system is associated with altered inflammatory responses in the heart and lung following IH exposure. Our study provides novel insight into the pathophysiological mechanisms associated with IH and potential biomarkers for the identification of comorbid cardiopulmonary pathology. Support (if any) National Institutes of Health grants 5K08HL148551; Triological Society; and the CCHMC Procter Scholar Award.