Nocturnal noise knocks NOS by Nox: mechanisms underlying cardiovascular dysfunction in response to noise pollution
Year: 2018
Type: editorial
Abstract: This editorial refers to ‘Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation’†, by S. Kröller-Schön et al., on page 3528. While common factors such as hypertension, hypercholesterolaemia, smoking, diabetes, diet, and physical inactivity account for a large majority of cardiovascular disease, there remain novel risk factors that are less well understood and characterized. With increasing urbanization, one such factor is the level of ambient noise in our environment, and particularly night-time noise that disturbs sleep. In the current issue of the European Heart Journal, Kröller-Schön et al. provide new evidence that noise, and particularly noise during sleeping hours, has a major impact on cardiovascular function, gene expression, and systemic parameters associated with vascular disease.1 These investigators exposed mice to around-the-clock aircraft noise, similar to that often encountered in our urban environments, and showed that this raised blood pressure, altered glucose levels, impaired endothelium-dependent vasodilatation, and augmented vascular, cerebral, and systemic oxidant stress. Noise exposure also seemed to cause an inflammatory response as evidenced by an elevation of circulating interleukin-6 (IL-6). These effects persisted and in most cases worsened from 1 to 4 days, and, interestingly, were reduced or absent in mice lacking the NADPH oxidase subunit Nox2. Kröller-Schön et al. also showed that an overnight exposure to aircraft noise increased plasma markers of oxidative stress in humans, providing evidence that this is an important clinical concern. Using unbiased gene expression profiling, the authors showed that noise exposure markedly altered the mRNA expression profile in the aorta, heart, and kidney. As typical of such analyses, numerous genes were either down- or up-regulated by noise exposure; however, bioinformatic analysis identified vascular circadian clock genes, including Npas2, Arnt1, Bmal1, Cry1, Per1, Cul1, and Prlag1/2, as being most affected by noise. In most cases (except for Per1), these were up-regulated by 10–50% in the aorta significantly after 1 day of noise exposure. Why would such genes in the aorta and other peripheral tissues be so affected by noise, which is at least initially perceived by the brain? Normally, sleep cycles and the associated changes in physiological rhythms are controlled by a set of genes collectively referred to as the central clock, located in the suprachiasmic nucleus.2 The suprachiasmic nucleus in turn receives input from light sensed by the retina through the retinohypothalamic tract, leading to modulation of sleep–awake cycles and other circadian behaviour. The central clock subsequently synchronizes expression of genes in peripheral tissues referred to as the peripheral clocks, comprised of aryl hydrocarbon receptor nuclear translocator-like protein (Arntl1, also called Bmal1), circadian locomotor output cycles kaput (Clock), Period (Per), and cryptochrome (Cry). Peripheral clocks are also controlled by other Zeitgeber cues independent of light, such as food intake or activity. The findings of Kröller-Schön et al. indicate that noise exposure profoundly affects these pathways (Take home figure). While the authors did not precisely examine circadian variation of various vascular clock genes, they show a co-ordinated dysregulation of their expression caused by noise. The down-regulation of Per1 observed by the authors is of interest, because Per1 and its homologues form a complex with Cry to inhibit Bmal/Clock function and expression. Paradigm illustrating the effects of noise on cardiovascular function. Increased ambient noise exposure, particularly during sleeping hours, results in dysregulation of the central circadian clock, which through an undefined mechanism causes uncoupling of nNOS in the brain, leading to augmented ROS production. This is followed by alteration in expression and function of peripheral clock genes, which in turn augment production of reactive oxygen species in the vasculature through both the Nox2-based NADPH oxidase and eNOS uncoupling, resulting in endothelial dysfunction and increased blood pressure. Noise exposure also leads to downstream systemic inflammation, oxidant stress, and impaired glucose homeostasis. Kröller-Schön et al. found that major consequences of noise exposure were systemic, central nervous system, and vascular oxidant stress, as evidenced by increases in vascular and brain superoxide production and plasma nitrotyrosine levels. This finding is in keeping with a growing literature showing that peripheral circadian clocks modulate vascular production of reactive oxygen species (ROS) in part by affecting coupling of the nitric oxide synthase (NOS) enzymes. These enzymes, which normally produce nitric oxide, can become ‘uncoupled’ in the absence of their critical cofactor tetrahydrobiopterin and their substrate l-arginine. In NOS, electrons that flow to l-arginine are diverted to molecular oxygen to form superoxide. Anea et al. have shown that vascular tetrahydrobiopterin levels are reduced in Bmal1-deficient mice, and that this uncouples the endothelial NOS.3 These authors provided evidence that this was in part due to oxidation of tetrahydrobiopterin to dihydrobiopterin, and also that enzymes responsible for tetrahydrobiopterin levels, GTP cyclohydrolase-1 and dihydrofolate reductase, exhibited circadian behaviour. Treatment with tetrahydrobiopterin improved endothelium-dependent vasodilatation and reduced vascular superoxide in the Bmal1-deficient mice. Many years ago, we showed that ROS from the NADPH oxidase can oxidize tetrahydrobiopterin, leading to hypertension.4 Likewise, we and others have shown that ROS from the NADPH oxidase can promote mitochondrial ROS formation and vice versa.5 , 6 Thus, the findings of Kröller-Schön et al., suggesting roles for the NADPH oxidase, uncoupled NOS, and the mitochondria as sources of ROS in response to noise exposure, are in keeping with the known interplay of these sources. Bioinformatic analysis of the next-generation sequencing results of Kröller-Schön et al. revealed FoxO transcription factors as a central signalling hub. Reasoning that Bmal1 contains a binding site for FoxO3, the investigators employed the calcium channel antagonist, anti-anginal drug bepridil, as a FoxO3 activator and found that this slightly reduced vascular and brain ROS formation and modestly enhanced endothelium-dependent vasodilatation. The use of bepridil as a FoxO3 agonist is based on one report in breast cancer cells,7 and it is possible that other calcium channel antagonists would have similar effects. Calcium channel antagonists lower blood pressure, and inhibition of calcium entry might alter NOS and NADPH oxidase activation via a variety of mechanisms. Nevertheless, use of drugs such as bepridil might provide a therapeutic approach for individuals with unavoidable exposure to noise pollution. The study by Kröller-Schön et al. highlights the role of sleep phase noise exposure on ROS production and blood pressure. The investigators found that noise during sleeping hours had a greater effect than during waking hours on several parameters studied. In large prospective studies, sleep deprivation has been identified as an independent risk factor for the development of cardiovascular disease. Deng et al. reported that <6 h of sleep per day increased the risk of obesity, glucose elevation, dyslipidaemia, and elevated blood pressure in a cross-sectional analysis of >160 000 Taiwanese adults.8 Conversely, Hoevenaar-Blom et al. found that sleeping >7 h per day resulted in a 65% lower risk of composite cardiovascular disease and an 83% lower risk of fatal cardiovascular disease.9 While not specifically measured in the study by Kröller-Schön et al., it is likely that sleep phase noise affects the circadian variation of blood pressure. In 1989, O’Brien etal. identified a subgroup of hypertensive patients who exhibited <10/5 mmHg decreases in pressure during sleep and termed these ‘non-dippers’.10 Non-dipping is present in ∼20–40% of patients with hypertension,11 and has been associated with cardiac remodelling, cerebrovascular damage, microalbuminuria, and cardiovascular mortality.12 , 13 There is also evidence that nocturnal hypertension (systolic BP >126 mmHg) with or without dipping during sleep is predictive of cardiovascular disease.14 A recent meta-analysis revealed that nocturnal hypertension is a risk factor for overall mortality and that once adjusted for night time blood pressure, daytime blood pressure no longer shows a significant association with cardiovascular events.15 Thus, sleep disruption by noise can have huge cardiovascular effects, in part via mechanisms such as those illustrated by Kröller-Schön et al. This work was supported by National Heart Lung and Blood Institute at the National Institutes of Health grants R35HL140016 and P01HL129941, and the American Heart Association Strategically Focused Research Network grant 14SFRN20420046. D.M.P. is supported by the National Institutes of Health T32 GM007569. Conflict of interest: none declared.
Source: European Heart Journal
Authors: David M Patrick, David G Harrison
Institution: Vanderbilt University Medical Center
Language: English
Topic: Noise Effects and Management
Subfield: Speech and Hearing
Field: Health Professions
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2883525362