Regulation of hypoxia‐inducible factor‐α isoforms and redox state by carotid body neural activity in rats

Abstract

Key pointsr Rats exposed to chronic intermittent hypoxia (CIH) exhibited imbalanced expression of hypoxia-inducible factor (HIF)-α isoforms and oxidative stress in brainstem regions associated with the carotid body (CB) chemoreflex, and in the adrenal medulla, an end organ of the sympathetic nervous system. r Selective ablation of the CB abolished the effects of CIH on HIF-α isoform expression and oxidative stress.r In the adrenal medulla, chemoreflex-mediated sympathetic activation regulates HIF-α isoform expression via muscarinic acetylcholine receptor-mediated Ca 2+ influx and the resultant activation of the mammalian target of rapamycin pathway and calpain proteases.r Thus, CB neural activity regulates HIF-α isoform expressions and redox state in the central and peripheral nervous system associated with the chemoreflex pathway under the setting of CIH.Abstract Previous studies reported that chronic intermittent hypoxia (CIH) results in an imbalanced expression of hypoxia-inducible factor-α (HIF-α) isoforms and oxidative stress in rodents, which may be due either to the direct effect of CIH or indirectly via hitherto uncharacterized mechanism(s). As neural activity is a potent regulator of gene transcription, we hypothesized that carotid body (CB) neural activity contributes to CIH-induced HIF-α isoform expression and oxidative stress in the chemoreflex pathway. Experiments were performed on adult rats exposed to CIH for 10 days. Rats exposed to CIH exhibited: increased HIF-1α and decreased HIF-2α expression; increased NADPH oxidase 2 and decreased superoxide dismutase 2 expression; and oxidative stress in the nucleus tractus solitarius and rostral ventrolateral medulla as well as in the adrenal medulla (AM), a major end organ of the sympathetic nervous system. Selective ablation of the CB abolished these effects. In the AM, sympathetic activation by the CB chemoreflex mediates CIH-induced HIF-α isoform imbalance via muscarinic acetylcholine receptor-mediated Ca 2+ influx, and the resultant activation of mammalian target of rapamycin pathway and calpain proteases. Rats exposed to CIH presented with hypertension, elevated sympathetic activity and increased circulating catecholamines. Selective ablation of either the CB (afferent pathway) or sympathetic innervation to the AM (efferent pathway) abolished these effects. These observations uncover CB neural activity-dependent regulation of HIF-α isoforms Abbreviations Ac-LLM-CHO, N-acetyl-leucine-leucine-methionine-aldehyde; AChR, acetylcholine receptor; AIH, acute intermittent hypoxia; AM, adrenal medulla; ASA, adrenal sympathetic ablation; BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N ,N -tetraacetic acid; BP, blood pressure; CA, catecholamines; CB, carotid body; CBA, carotid body ablation; CIH, chronic intermittent hypoxia; HIF-α, hypoxia-inducible factor alpha; HR, heart rate; mAChR, muscarinic ACh receptor; MDA, malondialdehyde; mTOR, mammalian target of rapamycin; nAChR, nicotinic ACh receptor; Nox2, NADPH oxidase 2; nTS, nucleus tractus solitarious; PC12, phe...

N‐Acetylcysteine reduces hyperacute intermittent hypoxia‐induced sympathoexcitation in human subjects

“…Although human studies do not permit us to achieve such a distinction, an intact carotid body (Kumar & Prabhakar, 2007; Semenza & Prabhakar, 2015) and neural chemoreflex arc (Peng et al , 2013; Peng et al , 2014) are required to mediate the hypertension observed in CIH conditioned rodents. However, it has been reported that hyper-acute intermittent optogenetic stimulation of NTS neurons increase renal SNA in a fashion similar to hAIHT (Yamamoto et al , 2015), indicating that neither hypoxia, chemoreceptor stimulation nor peripherally generated oxidative stress are required to produce the sympathetic dysregulation observed with hAIHT.…”

“…The findings of these studies demonstrate that ROS generated at the carotid body, in the nucleus of the solitary tract (NTS) and within the rostral ventral lateral medulla (RVLM) in response to chronic intermittent hypoxia (CIH; i.e. 3–14 days of IH exposure) elicits increases in sympathetic nerve activity (SNA) and hypertension (Peng et al , 2011; Peng et al , 2013; Peng et al , 2014). Further, it has been reported that antioxidant administration substantially reduces the efflux of catecholamines from ex-vivo adrenal medullae in rats conditioned to CIH (Kumar et al , 2006).…”

“…Further, it has been reported that antioxidant administration substantially reduces the efflux of catecholamines from ex-vivo adrenal medullae in rats conditioned to CIH (Kumar et al , 2006). In addition, CIH has been found to reduce the activities of critical antioxidant enzymes in the carotid body, the NTS and RVLM (Peng et al , 2011; Peng et al , 2013; Peng et al , 2014). Human (Foster et al , 2010; Pialoux et al , 2011) and animal (Marcus et al , 2010) studies have demonstrated that oxidative stress is also elevated after acute intermittent hypoxia (AIH; i.e.…”

Humans In Hypoxia: A Conspiracy Of Maladaptation?!

“…This imbalance in the HIF isoforms results in extraordinarily high levels of ROS in the carotid chemoreceptor glomus cells, which increases carotid sinus nerve activity, leading over time to enhanced activity of neurons in downstream elements of the carotid chemoreflex pathway, i.e., in the NTS, RVLM, and paraventricular nucleus of the hypothalamus (55,87,102,106,108). The enhanced chemoreceptor sensitivity and sympathoexcitation that occur during IH persist upon reoxygenation well beyond the nocturnal IH exposure.…”

Sex, stress and sleep apnoea: Decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females

“…Indeed, animal models of CIH recapitulate many of the morbidities reported in OSAS patients, thereby serving as a useful model of the disease (Chopra et al, 2016;O'Halloran, 2016). There is strong evidence that CIH alters cardiorespiratory control, through adverse actions at multiple sites in the integrative control network (Peng et al, 2003(Peng et al, , 2006(Peng et al, , 2014Rey et al, 2004;Julien et al, 2008;Del Rio et al, 2010;Moraes et al, 2013;Zanella et al, 2014;Garcia et al, 2016), disrupting the rhythm and pattern Zanella et al, 2014;Garcia et al, 2016) of central respiratory drive, with evidence of increased propensity for central apnoea following CIH exposure Donovan et al, 2014;Souza et al, 2015) Fibre type transitions have been described in some studies (Pae et al, 2005;Liu et al, 2009), but it appears that upper airway muscle dysfunction is not dependent on fibre-type remodelling or atrophy (Skelly et al, 2012a), phenotypic differences that are perhaps dependent on the experimental paradigm employed in the studies, which varies considerably in terms of pattern, duration and intensity of hypoxic exposure. An increase in the proportion of fast fatiguable 2B fibres was observed by Pae et al (2005), consistent with observations of decreased muscle endurance (Pae et al, 2005), a finding which resonates with observations of slow-to-fast fibre transitions in OSAS (Series et al, 1995(Series et al, , 1996a, and increased relative area of fast fibres in an upper airway muscle of the English bulldog (Petrof et al, 1994), a model of OSAS.…”