Epigenetic influences on carotid body function: a new snag in the road to treating sleep apnoea

Sleep apnoeas, both obstructive and central, are a major health risk for cardiovascular disease, stroke, diabetes, depression and other serious conditions. The prevalence of sleep disordered breathing is conservatively estimated at 1 in 5 adult men and 1 in 10 women, and this estimate continues to rise as better standards are established to recognize and diagnosis the disorder. Although risks factors such as weight, sex, age and comorbid disease conditions are well defined, the causes for the underlying pathophysiological consequences of sleep apnoea continue to be debated. In 1992 a landmark study (Fletcher et al. 1992) revealed that intermittent hypoxic (IH) episodes, mimicking those derived from repetitive apnoeas, are a potent stimulus for the development of hypertension in rats and that carotid body ablation prevented the hypertension. This study set into motion several theories over the past 24 years to define how carotid body function is altered by IH. These theories include oxidative stress and changes in oxygen sensing pathways in the carotid body driven by redox sensitive enzymes and transcription factors (Prabhakar, 2013).

In the absence of a clear molecular understanding of the causes and consequences of sleep apnoeas, the principal therapeutic approach to treating the disorder has been to prevent the apnoeas, and thus the consequences of IH, through device intervention. Continuous positive airway pressure (CPAP), oral appliances, stimulation devices and surgical interventions are available options, with CPAP as the gold standard. Unfortunately, in clinical studies the efficacy of these techniques in reducing the health risks of sleep apnoea has not been as promising as anticipated. From a therapeutic perspective, preventing IH per se may not be adequate to reverse the pathophysiological consequences of sleep apnoea disorders.

An article published in a recent issue of The Journal of Physiology entitled ‘Epigenetic regulation of redox state mediates persistent cardiorespiratory abnormalities after long‐term intermittent hypoxia’ (Nanduri et al. 2017) provides important new insights into this paradox. This study reveals that the hypertension, irregular apnoeic breathing and the augmented carotid body chemosensory reflexes associated with IH in rats are normalized following recovery from short term (10 days) IH, but not from long term (30 days) IH. In other words, the cardiorespiratory abnormalities that occur during long term IH are permanent, even 30 days after removing the IH stimulus. Importantly, this study further demonstrates that the persistent cardiorespiratory responses following long term IH are associated with elevated oxidative stress in the carotid body and adrenal medulla due to DNA methylation‐dependent suppression of genes encoding anti‐oxidant enzymes in these tissues. When DNA methylation was prevented by treating IH rats with decitabine, the intervention reversed the suppression of anti‐oxidant enzymes and normalized carotid body chemosensory reflex, blood pressure and breathing stability following IH.

An important outcome of this study is that exposure to long term IH can lead to irreversible suppression of anti‐oxidant genes and elevated ROS levels in the carotid body and adrenal medulla long after removal of the IH stimulus. These ‘permanent’ changes in redox state then cause persistent activation of the carotid body chemoreflex and adrenal medulla noradrenaline (norepinephrine) release with associated cardiorespiratory derangements that continue long after removing the IH state. These observations may be relevant to understanding why the cardiorespiratory abnormalities in sleep apnoea patients are often resistant to CPAP therapy, which serves only to eliminate IH. It is also noteworthy that the detrimental cardiorespiratory effects of IH are readily reversible if animals are exposed to IH for a much shorter term, before DNA methylation ensues. If there is a clinical lesson to be learned from the present study (Nanduri et al. 2017), it is that the history of onset of sleep apnoea in patients is likely to have a direct impact on the efficacy of treatment. However, this prognostic tool is nearly impossible to gauge because onset of sleep apnoea is not possible to detect with usual medical evaluation and history. In most cases, it is probable that once sleep apnoea is diagnosed in a patient, they may be beyond the point of effective treatment by present means.

Most importantly, the study by Nanduri et al. (2017) explains why the carotid body and adrenal medulla are permanently altered in chronic IH. This study provides the first ever evidence for an epigenetic alteration in gene expression of anti‐oxidant enzymes in these tissues via DNA hypermethylation to alter function. DNA methylation is not inherently bad, and in fact it is essential for mammalian development. This system determines when and where a particular gene will be expressed during development and is a potent mechanism for silencing gene expression and maintaining genome stability in the face of a vast quantity of repetitive DNA. However, there is a rapidly expanding awareness that many human diseases are induced or exacerbated when this epigenetic information is not properly established and maintained. Although emphasis has been placed on the impact of anomalous DNA methylation on diseases of genomic imprinting and its role in a ‘fetal stress origin’ of adult‐onset disease, the present study illustrates that aberrant DNA methylation can occur in adult life in response to prolonged exposure to an environmental stressor to produce impaired organ function – in this case, DNA hypermethylation occurs in response to intermittent hypoxia resulting in aberrant carotid body chemoreflex influence on cardiorespiratory function. By inference, we must now consider not only epigenetic influences that may drive the development of sleep apnoea in humans but also the epigenetic consequences of sleep apnoea that help drive the development of cardiovascular disease.

Additional information

Competing interests

None declared.

Funding

The author is supported by the NIH (National Heart, Lung, and Blood Institute; PO1‐HL62222).