Obstructive sleep apnea causes widespread gene disruption in mice throughout the day

Studies using a mouse model of obstructive sleep apnea (OSA) show that the low blood oxygen level (hypoxia) caused by this condition broadly affects gene activity in various tissues throughout the day. It suggests that it can cause change. The results of this study, conducted by scientists and colleagues at the Cincinnati Children’s Hospital Medical Center, show that transcriptomic changes in cardiopulmonary tissue influence the effects of the resulting intermittent hypoxia (IH) more than other tissues. showed strong acceptance. The overall study results could lead to the development of tools for early diagnosis and follow-up of OSA, the research team suggested.

Researchers led by Dr. David Smith reported on their findings: PLOS biologyIn an article titledObstructive sleep apnea in a mouse model is associated with tissue-specific transcriptome changes in circadian rhythm and mean 24-h gene expressionThey wrote in their paper, “In summary, our findings demonstrate a unique relationship between early IH exposure and distinct alterations in biological pathways that contribute to physiological outcomes… Our findings provide new insights into the pathophysiological mechanisms that may be associated with end-organ injury.” in patients chronically exposed to IH. ”

Obstructive sleep apnea is a disorder in which the airways (usually obstructed by soft tissue and accompanied by nocturnal snoring and breathing interruptions) result in intermittent hypoxia or low blood oxygen levels that disrupt sleep. Occurs when interrupted. The authors cited figures showing that the condition affects more than 1 billion people worldwide and costs $150 billion annually in direct medical costs in the United States alone. IH associated with OSA increases the risk of cardiovascular, respiratory, metabolic, and neurological complications.

The authors explained that in patients with OSA, IH occurs only during the sleep phase of the 24-h sleep-wake cycle, which may alter the physiological circadian rhythm. “The circadian clock is a molecular oscillator that uses positive and negative transcriptional and translational feedback loops of core clock components. Because the circadian clock serves as a timekeeper for molecular, cellular, organ, and physiological functions, , is one of the key components in maintaining whole-body homeostasis” process. ”

The activity of many genes varies naturally throughout the day, in part in response to the activity of circadian clock genes. Regular oscillations of circadian clock genes drive circadian fluctuations in the largest half of the genome. However, the researchers point out that the circadian clock can be disturbed by internal factors (such as health conditions) or external factors (such as the living environment). External factors that can affect gene activity include reduced oxygen levels that cause the production of hypoxia-inducible factors that affect the activity of many genes, including clock genes.

To gain a deeper understanding of how OSA affects gene activity throughout the day, the authors exposed mice to intermittent hypoxia and tested their lung, liver, kidney, muscle, heart, and cerebellum. Whole-genome transcripts in six tissues were examined throughout the day. The authors then assessed variations in the circadian timing of gene expression in these same tissues. “Since chronic untreated OSA is primarily associated with adverse cardiopulmonary effects, we hypothesized that IH might affect biological processes in the lung and heart more rapidly than in other tissues. ‘, the researchers commented.

The results showed that the greatest changes were in the lung, where intermittent hypoxia affected the transcription of nearly 16% of all genes, most of which were upregulated. Just under 5% of genes were affected in heart, liver and cerebellum. A subset of genes that normally exhibit circadian rhythms are more strongly affected by intermittent hypoxia, with 74% of such genes in the lung and 66.9% of such genes in the heart being profoundly altered. I was. Among the genes affected in each tissue are known clock genes, whose effects may contribute to the large changes in circadian activity of other genes seen in these tissues. The team then used transcriptome changes to examine changes in biological processes and physiological changes in mammals. “The results suggest that the transcriptome of cardiopulmonary tissue and its associated biological processes were affected to a greater extent compared to the other tissues evaluated,” the researchers noted. . “Our findings show a relationship between her early exposure to IH and changes in specific physiological outcomes.”

Co-author Dr. Bala SC Koritala said: “Our studies using an animal model of obstructive sleep apnea have revealed time- and tissue-specific mutations in characteristic pathways associated with the genome-wide transcriptome. The findings reveal early biological changes associated with this disease that occur across multiple organ systems.”

They noted that “a key challenge in preventive care for patients with OSA is ‘early diagnosis’, before associated comorbidities develop.” They suggest that data from the newly reported study provide insight into early changes in relevant biological pathways. “Our findings show that there are time- and tissue-specific variations in the whole-genome transcriptome in multiple organ systems, even with brief exposure to IH, and that the lung transcriptome compared with other organs was significantly more sensitive to the lung transcriptome than in other organs.” suggests that are most affected.

“Our findings provide new insight into the pathophysiological mechanisms that may be associated with end-organ damage in patients chronically exposed to intermittent hypoxia,” Smith added. It may help identify targets for future mechanistic studies evaluating diagnostic or therapeutic approaches.” For example, it detects early OSA through a blood test that tracks one of the dysregulated gene products.