Expressions of angiotensin and cytokine receptors in the paracrine signaling of the carotid body in hypoxia and sleep apnea

https://doi.org/10.1016/j.resp.2014.09.014Get rights and content

Highlights

  • Angiotensin and cytokine receptors expressed in the carotid body play roles in modulating carotid chemoreceptor activities.

  • Elevated expressions of angiotensin receptors and local angiotensin-generating system in the carotid body (CB) in hypoxia.

  • Carotid body inflammation involves elevated local expressions of pro-inflammatory cytokines and cytokine receptors in hypoxia.

  • Upregulated angiotensin and cytokine pathways augment chemoreceptor activities and mediate CB inflammation in sleep apnea.

Abstract

Arterial chemoreceptors in the carotid body are central to the chemical control of breathing in the chemotransduction of physiological stimuli in the arterial blood for eliciting the chemoreflex, which mediates the respiratory, cardiovascular and autonomic responses to hypoxia, hypercapnia and acidosis. Recent evidence suggests that signaling molecules locally produced in the carotid body, including angiotensin II and pro-inflammatory cytokines play an important role in the modulation of the activity of carotid chemoreceptors, via the angiotensin and cytokine receptors expressed in the chemosensitive cells in an autocrine–paracrine manner. The carotid chemoreceptor activity is augmented in subjects at high altitude and in patients with sleep-disordered breathing. Maladaptive responses of the paracrine signaling to hypoxia in the carotid body have been proposed to play a pathogenic role in sleep apnea. Specifically, recent findings show significant increases in expressions of angiotensin receptors and components of a local angiotensin-generating system in the carotid body in sustained or intermittent hypoxia, which augments the chemoreceptor activity and also mediates the inflammatory response of the carotid body to hypoxia. In addition, inflammation of the carotid body involves an increased local expression of cytokine receptors and pro-inflammatory cytokines in sustained or intermittent hypoxia. This review aims to summarize the evidence supporting that the upregulated expression of the angiotensin receptors and cytokine pathways in the carotid body leads to augmented activities of the carotid chemoreceptor in hypoxic conditions, which could play a role in the pathophysiology of sleep apnea.

Introduction

Arterial chemoreceptors in the carotid body, located bilaterally at the bifurcation of the carotid artery, are responsive to chemical changes in the arterial blood, which are essential to elicit the chemoreflex for the maintenance of the blood gases and pH homeostasis. The carotid body is innervated by chemoafferent fibers of the carotid sinus nerves, which project the sensory activity via the glossopharyngeal nerve to the medullary neurons in the nucleus tractus solitary for eliciting the central efferent outputs of the chemoreflex. Increased central respiratory activities and altered autonomic activities are responsible for the ventilatory and circulatory responses to hypoxia, including but not limited to hyperventilation, bradycardia and redistribution of blood flow to vital organs. Thus, resection of the carotid body greatly diminishes the ventilatory response to hypoxia in human subjects (Teppema and Dahan, 2010).

The carotid chemoreceptor is composed of chemosensitive glomus (type-I) cells apposed to nerve endings of petrosal ganglionic neurons. The glomic clusters are also encompassed by sustentacular (type-II) cells and are proximal to highly dense capillaries supplied with blood perfusion far exceeding the metabolic rate of the carotid body (Gonzalez et al., 1994, Lahiri et al., 2001). Thus, chemical stimuli in the arterial blood and signaling molecules locally produced in the carotid body are within a diffusing distance of equilibrium effecting on the chemosensory component of the carotid body. Chemotransduction is mainly mediated by type-I cells which biosynthesize and release a number of neurotransmitters including acetylcholine, ATP, catacholamines, and also neuromodulators including neuropeptides and adenosine in responding to physiological stimuli including hypoxia, hypercapnia and acidosis (Nurse, 2010). More recently, type-II cells are also believed to play an active role in the local regulation of the chemosensory process, mediated by the ATP release from these cells as a paracrine signal to modulate the activity of type-I cells via purinergic pathways (Nurse, 2014).

Moreover, the carotid chemoreceptor is responsive to circulating hormones including angiotensin II, inflammatory and immunogenic signaling molecules including pro-inflammatory cytokines and lipopolysaccharides (LPS) because the corresponding receptors are expressed in the carotid body. In addition, recent findings suggest that a number of vasoactive peptides, including angiotensin II and endothelin-1, and pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, are produced locally in the carotid body. Evidence suggests that these signaling molecules modulate the activity of the carotid chemoreceptor in a paracrine–autocrine manner (Fung et al., 2014). More importantly, these local mechanisms are regulated by hypoxia, as in sustained hypoxia relevant to the physiological acclimation to altitudes and also in intermittent hypoxia relevant to sleep apnea in disease conditions. Thus it has been recently proposed that alterations of the expression of the receptors of these paracrine–autocrine signaling molecules by hypoxia play roles in the inflammatory response of the carotid body to hypoxia and also in the augmented activity of the carotid chemoreceptor, which could be functionally important in the ventilatory acclimation to hypoxia and also in the pathophysiology of sleep apnea (Fung et al., 2014). This review aims to summarize recent findings in the literature focusing on the hypoxic regulation of the expression of angiotensin and cytokine receptors in the paracrine signaling of the carotid body under hypoxic conditions relevant to sleep apnea.

Section snippets

Expression of angiotensin receptors in the carotid body

Carotid chemoreceptors are responsive to angiotensin II because angiotensin (AT) receptors are expressed in the carotid body. Morphological studies have demonstrated that the AT receptor–ligand binding is present in the carotid body with or without sympathetic or afferent denervation, suggesting the expression of AT1 receptors in the chemosensory component of the carotid body (Allen, 1998). Positive AT1-immunoreactivity is found in the rat carotid body although it is not ubiquitously expressed

Expression of receptors of pro-inflammatory cytokines in the carotid body

The carotid chemoreceptor is responsive to pro-inflammatory cytokines because of the expression of cytokine receptors in the carotid body, which plays a role in the immune-to-brain communication of the inflammatory and infective status (Zapata et al., 2011, Porzionato et al., 2013). It has been shown that IL-1 receptor type I (IL-1r1) is expressed in the type-I cells of the carotid body (Wang et al., 2002, Lam et al., 2008, Lam et al., 2012). The receptor is functional because the outward

Hypoxia upregulates the expression of angiotensin receptors in the carotid body

The mRNA and protein expressions of AT1 and AT2 receptors in the carotid body are significantly increased in the carotid body of rats exposed to sustained hypoxia (10% inspired oxygen for weeks), which are colocalized in type-I cells containing tyrosine hydroxylase (Leung et al., 2000, Fung et al., 2002). The increased expression results in doubling the amount of type-I cells and carotid chemoreceptors responding to angiotensin II to 80% in sustained hypoxia (Leung et al., 2000, Fung et al.,

Hypoxia upregulates expressions of cytokine receptors in the carotid body

Evidence supports that hypoxia regulates the cytokine signaling pathway in the carotid body. It has been reported that plasma levels of cytokines are elevated in altitude natives and subjects sojourning at high altitude under a sustained hypoxic condition (Keatings et al., 1996, Mazzeo et al., 2001, Bucchioni et al., 2003). In patients, chronic inflammation is a clinical manifestation in diseases associated with chronic hypoxemia (Wouters, 2005, Celli and Barnes, 2007). Studies have shown that

Upregulated expression of angiotensin receptors in intermittent hypoxia relevant to sleep apnea

Recurrent episodes of hypopnea or apnea in sleep cause intermittent hypoxia, which significantly contributes to the pathophysiological consequences of sleep apnea (Fletcher, 2001, Del Rio et al., 2010, Dempsey et al., 2010, Prabhakar and Semenza, 2012). Thus, intermittent hypoxia induces significant elevated levels of arterial pressures (Fletcher et al., 1992a, Fletcher et al., 1992b), sympathetic activities (Greenberg et al., 1999, Fletcher, 2003), catecholamines (Bao et al., 1997),

Upregulation of cytokine receptors and cytokines in intermittent hypoxia

The mRNA and protein expressions of IL-1r1, gp130 and TNF-r1 are significantly increased in type-I cells in the carotid body of rats exposed to intermittent hypoxia equivalent to a severe condition of sleep apnea for days to weeks (Del Rio et al., 2012a, Lam et al., 2012). Also intermittent hypoxia induces elevated levels of the expression of IL-1β, IL-6 and TNFα in the carotid body (Del Rio et al., 2012a, Lam et al., 2012). The number of cells with the expression of the cytokine receptors and

Summary and conclusion

Fig. 1 summarizes the role of expressions of angiotensin and cytokine receptors in the carotid body. Firstly these receptors expressed in the chemosensitive cell play functional roles in the carotid chemoreceptor response to circulating angiotensin II and cytokines, which activate the chemoafferent activity and the chemoreflex under disease or infectious conditions. More importantly, these receptors are an integral part of the paracrine signaling pathway in the carotid body regulated by

Acknowledgments

Studies were supported by grants from the Research Grants Council, Hong Kong (HKU 766110M, HKU 7510/06M) and internal funding from the University Research Committee, HKU.

References (79)

  • N.J. Marcus et al.

    Chronic intermittent hypoxia augments chemoreflex control of sympathetic activity: role of the angiotensin II type 1 receptor

    Respir. Physiol. Neurobiol.

    (2010)
  • D.S. Moller et al.

    Abnormal vasoactive hormones and 24-hour blood pressure in obstructive sleep apnea

    Am. J. Hypertens.

    (2003)
  • D. Popa et al.

    Ibuprofen blocks time-dependent increases in hypoxic ventilation in rats

    Respir. Physiol. Neurobiol.

    (2011)
  • A. Porzionato et al.

    Inflammatory and immunomodulatory mechanisms in the carotid body

    Respir. Physiol. Neurobiol.

    (2013)
  • P. Zapata et al.

    Immunosensory signalling by carotid body chemoreceptors

    Respir. Physiol. Neurobiol.

    (2011)
  • A.M. Allen

    Angiotensin AT1 receptor-mediated excitation of rat carotid body chemoreceptor afferent activity

    J. Physiol.

    (1998)
  • G. Bao et al.

    Blood pressure response to chronic episodic hypoxia: role of the sympathetic nervous system

    J. Appl. Physiol.

    (1997)
  • A. Barcelo et al.

    Angiotensin converting enzyme in patients with sleep apnoea syndrome: plasma activity and gene polymorphisms

    Eur. Respir. J.

    (2001)
  • P.J. Barnes et al.

    Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases

    New Eng. J. Med.

    (1997)
  • G. Bonizzi et al.

    Reactive oxygen intermediate-dependent NF-kappaB activation by interleukin-1beta requires 5-lipoxygenase or NADPH oxidase activity

    Mole. Cell Biol.

    (1999)
  • J. Chen et al.

    Role of endothelin and endothelin A-type receptor in adaptation of the carotid body to chronic hypoxia

    Am. J. Physiol. Lung Cell. Mol. Physiol.

    (2002)
  • Y. Chen et al.

    Chronic hypoxia enhances endothelin-1-induced intracellular calcium elevation in rat carotid body chemoreceptors and up-regulates ETA receptor expression

    Pflügers Arch. Eur. J. Physiol.

    (2002)
  • B.R. Celli et al.

    Exacerbations of chronic obstructive pulmonary disease

    Eur. Respir. J.

    (2007)
  • S.Y. Chai et al.

    The angiotensin IV/AT4 receptor

    Cell. Mol. Life Sci.

    (2004)
  • R. Del Rio et al.

    Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link

    Eur. Respir. J.

    (2010)
  • R. Del Rio et al.

    Carotid body inflammation and cardiorespiratory alterations in intermittent hypoxia

    Eur. Respir. J.

    (2012)
  • R. Del Rio et al.

    Contribution of inflammation on carotid body chemosensory potentiation induced by intermittent hypoxia

    Adv. Exp. Med. Biol.

    (2012)
  • J.A. Dempsey et al.

    Pathophysiology of sleep apnea

    Physiol. Rev.

    (2010)
  • J. Fan et al.

    Interleukin-6 increases intracellular Ca2+ concentration and induces catecholamine secretion in rat carotid body glomus cells

    J. Neurosci. Res.

    (2009)
  • R. Fernández et al.

    Lipopolysaccharide-induced carotid body inflammation in cats: functional manifestations, histopathology and involvement of tumour necrosis factor-alpha

    Exp. Physiol.

    (2008)
  • E.C. Fletcher et al.

    Carotid chemoreceptors, systemic blood pressure, and chronic episodic hypoxia mimicking sleep apnea

    J. Appl. Physiol.

    (1992)
  • E.C. Fletcher et al.

    Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats

    Hypertension

    (1992)
  • E.C. Fletcher

    Invited review: physiological consequences of intermittent hypoxia: systemic blood pressure

    J. Appl. Physiol.

    (2001)
  • E.C. Fletcher

    Sympathetic overactivity in the etiology of hypertension of obstructive sleep apnea

    Sleep

    (2003)
  • M.L. Fung et al.

    Functional expression of angiotensin II receptors in type-I cells of the rat carotid body

    Pflugers Arch.

    (2001)
  • M.L. Fung et al.

    Postnatal hypoxemia increases angiotensin II sensitivity and up-regulates AT1a angiotensin receptors in rat carotid body chemoreceptors

    J. Endocrinol.

    (2002)
  • M.L. Fung et al.

    Carotid Body AT4 Receptor expression and its upregulation in chronic hypoxia

    Open Cardiovasc. Med. J.

    (2007)
  • M.L. Fung et al.

    Mechanisms of maladaptive responses of peripheral chemoreceptors to intermittent hypoxia in sleep-disordered breathing

    Sheng Li Xue Bao

    (2014)
  • C. Gonzalez et al.

    Carotid body chemoreceptors: from natural stimuli to sensory discharges

    Physiol. Rev.

    (1994)
  • Cited by (0)

    View full text