Nicotinic acetylcholine receptor α7 subunit: a novel therapeutic target for cardiovascular diseases

Abstract

Inflammation is important in the pathogenesis and development of cardiovascular diseases. Recent studies show that vagus nerve stimulation inhibits pro-inflammatory cytokine production through “the cholinergic anti-inflammatory pathway,” more specifically via the α7 nicotinic acetylcholine receptor (α7nAChR). In the current study, the role of the cholinergic anti-inflammatory pathway during septic shock, hypertension, and myocardial infarction is reviewed, and its possible clinical implications in cardiovascular diseases are discussed.

Keywords

α7 nicotinic acetylcholine receptor / cardiovascular diseases / baroreflex sensitivity

Introduction

Inflammation is a physiologic response to pathogen invasion and tissue damage. During the inflammatory process, the immune system releases cytokines, including tumor necrosis factor (TNF) and other mediators, to promote pathogen clearance and tissue repair. However, excessive cytokine release and prolonged inflammatory response cause tissue damage and could result in fatal organ failure in certain circumstances. Redundant inflammatory cytokines may allow a local inflammation to become an uncontrolled systemic inflammatory response [1]. Cardiovascular diseases are major threats to human health, and inflammation plays an important role in their pathogenesis and development [2, 3]. Recent studies have identified an efferent vagus nerve-based mechanism termed “the cholinergic anti-inflammatory pathway,” by which the pro-inflammatory cytokine production and inflammatory response can be modulated [4, 5]. In the current study, the recent findings in our laboratory regarding the cholinergic anti-inflammatory pathway and cardiovascular diseases are reviewed.

Cholinergic anti-inflammatory pathway

The interaction between the nervous and immune systems is vital in modulating the innate immune response and controlling inflammation. The link between the parasympathetic arm of the autonomic nervous system and the inflammatory regulatory process was suggested some 30 years ago [6]. The existence of a vagus nerve pathway for modulating systemic and local inflammatory responses has only been recently demonstrated [5]. The efferent vagus nerve controls the inflammatory response by specifically suppressing the overproduction and systemic release of pro-inflammatory cytokines (e.g. TNFα). This route is termed the “cholinergic anti-inflammatory pathway.” Stimulation of the efferent vagus nerve releases acetylcholine, which binds to the α7 nicotinic acetylcholine receptor (α7nAChR) on macrophages. Earlier experiments demonstrated that acetylcholine could attenuate the production of TNFα, interleukin (IL)-1β, IL-6, and IL-18 in endotoxin-stimulated human macrophage via a post-transcriptional mechanism. The fact that IL-10 release is not affected by acetylcholine suggests a direct inhibitory effect of acetylcholine on pro-inflammatory cytokine production. In an endotoxemia model, electrical stimulation of the cervical vagus nerve significantly reduced the serum and liver TNFα levels, prevented the development of hemodynamic shock, and improved survival without significantly altering IL-10 or corticosterone serum levels [5]. These results provided evidence of the role of the vagus nerve in controlling excessive inflammation. In the endotoxemia model, increased vagus nerve activity is necessary to counteract the exacerbated release of pro-inflammatory cytokines.

The molecular link between the brain and the immune system in the cholinergic anti-inflammatory pathway is the α7nAChR. Transfection of macrophages with specific antisense oligonucleotides against α7nAChR can attenuate the inhibitory effect of nicotine on TNFα release. Vagus nerve stimulation (VNS) fails to reduce the serum TNFα levels in α7nAChR knockout mice, indicating that α7nAChR is necessary for the proper functioning of the cholinergic anti-inflammatory pathway. α7nAChR knockout mice have significantly increased TNFα levels in the serum, spleen, and liver relative to the wild-type mice [7]. These results indicate that the cholinergic anti-inflammatory pathway tonically inhibits cytokine production and functions as an essential regulator of inflammation via α7nAChR.

α7nAChR is a ligand-gated ion channel and can exist in both homopentameric and heteropentameric forms [8]. The main function of this receptor is to transmit acetylcholine signals in the central and peripheral nervous systems [9]. Upon binding with acetylcholine, α7nAChR transmits cholinergic anti-inflammatory signals into the cytoplasm to activate Janus kinase 2 (JAK2). The phosphorylation of JAK2 subsequently triggers the phosphorylation of signal transducers and activators of transcription 3 (STAT3) and promotes its dimerization. Phosphorylated STAT3 translocates from the cytoplasm into the nucleus and competes with nuclear factor-κB (NF-κB) to bind DNA. This competition lowers the production of pro-inflammatory cytokines such as TNFα, IL-6, high-mobility group box 1 protein (HMGB1), and macrophage inflammatory protein-2 (MIP-2) [10]. However, recent studies also indicate that STAT3 can promote inflammation [11,12]. Therefore, the cholinergic anti-inflammatory pathway signals need to be further investigated.

Regulation of the cholinergic anti-inflammatory pathway

Decreased vagal function is associated with increased risk for morbidity and mortality in cardiovascular diseases, and an increased vagal function could lower the risk profiles [13]. The arterial baroreflex (ABR) is the most important mechanism regulating the vagal function. The function of the ABR, expressed by the baroreflex sensitivity (BRS), is impaired in aging, hypertension, heart failure, myocardial infarction, atherosclerosis, and diabetes. The impairment of the baroreflex in the aforementioned cardiovascular diseases is mainly due to the blunted parasympathetic component [14]. In other words, the reflex activity of the vagus nerve is diminished in cardiovascular diseases. The tonic activity of the vagus nerve is also diminished in hypertension and myocardial infarction [15, 16]. Ketanserin, a selective 5-hydroxytryptamine antagonist, can increase BRS through a central mechanism and has been proven the most effective drug for enhancing BRS and/or vagal activity [17]. In addition, many studies have shown that exercise, dietary restriction, and slow breathing significantly enhance BRS and/or vagal activity [18-20].

Another method of activating the vagal function is VNS using an electrical stimulator [21]. Drug stimulators (e.g. CNI-1493) can attenuate the production of TNFα in a wide range of conditions, from experimental stroke and sepsis in mice to inflammatory bowel diseases in humans [22, 23]. Recently, cholinesterase inhibitors were also used to stimulate vagal activity [24,25].

Activation of the cholinergic anti-inflammatory pathway can be accomplished through synthetic α7nAChR agonists such as PNU-282987([N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4- chlorobenzamide hydrochloride]), GTS21(3-[(2,4-dimethoxy)benzylidene]-anabaseine). These drugs have been developed for the treatment of neurodegenerative diseases and may also be useful for cardiovascular diseases [8]. A working hypothesis for the relationship between α7nAChR and cardiovascular diseases is shown in Fig. 1.

Cholinergic anti-inflammatory pathway and septic shock

Activation of α7nAChR via VNS or pharmacological agents attenuates the levels of pro-inflammatory cytokines and increases the survival rate in animal models of sepsis and lipopolysaccharide (LPS)-induced shock [26-29]. A recent study from this laboratory showed that anisodamine, a muscarinic receptor antagonist, could produce an antishock effect by activating α7nAChR [30]. Methyllycaconitine, a selective α7nAChR antagonist, attenuated the beneficial effects of anisodamine on the hemodynamics, pro-inflammatory cytokine levels, and survival in a murine endotoxic shock model. In unilateral vagotomized mice and α7nAChR knockout mice, the antishock effects of anisodamine were largely reduced. In RAW264.7 cells (a macrophage-like cell line derived from BALB/c mice) labeled with fluorescein isothiocyanate-tagged α-bungarotoxin, a peptide that competes with nicotine for binding to α7nAChR, anisodamine, augmented the binding of endogenous acetylcholine to the α7nAChR by blocking the muscarinic receptors. In acetylcholine-treated macrophages from wild-type mice, anisodamine significantly augmented the inhibitory effect of acetylcholine on TNFα production. However, this effect disappeared in α7nAChR knockout macrophages. These results indicate that the antishock effect of anisodamine is intimately linked to α7nAChR, and its mechanism of action on α7nAChR may be through the blockade of muscarinic receptors, thereby allowing increased endogenous acetylcholine binding to α7nAChR.

ABR dysfunction shortens the survival time in both LPS-induced and cecal ligation and puncture-induced lethal shock [31, 32]. Recent studies indicate that restoring an impaired ABR can be useful in the treatment of these two septic shock models. Ketanserin, which can increase BRS, lowers the mortality and prolongs the survival time in mice with intact ABR [33]. However, the effect is attenuated in sinoaortic denervated (SAD) mice. These results showed that the beneficial effect of ketanserin is mediated primarily through BRS enhancement. Recent findings demonstrated that parasympathetic tension, endogenous transmitter acetylcholine, and α7nAChR expression are all decreased in SAD rats. Therefore, the beneficial effect of ketanserin may be mediated by enhancing baroreflex and α7nAChR functions and increasing the parasympathetic activity.

Cholinergic anti-inflammatory pathway and hypertension

Inflammatory cytokines are significantly increased in the serum of hypertensive patients as well as in a variety of organs/tissues of hypertensive animals. These findings indicate that inflammatory responses are associated with the development and progression of end-organ damage (EOD) in hypertension. α7nAChR dysfunction may be involved in hypertensive EOD. Li et al. [15] discovered the blunted response of the heart rate to atropine in spontaneously hypertensive rats (SHRs). The expression of the vesicular acetylcholine transporter (VAChT) and α7nAChR in cardiovascular tissues in SHRs (20 and 40 weeks of age) is decreased compared with those in the age-matched Wistar Kyoto (WKY) rats. However, in juvenile SHRs (4 weeks of age) without hypertension, the expression of VAChT and α7nAChR was comparable to that in age-matched WKY rats. These results show that the decreased expression of VAChT and α7nAChR in SHRs is due to hypertension instead of differences in the genetic background. In a pressure-overload rat model of abdominal arterial coarctation, α7nAChR and VAChT were equally downregulated in the aortic segments proximal and distal to the coarctation. These results show that hypertension appears to exert a systemic effect by suppressing cholinergic signaling rather than exerting a local effect dependent on the level of arterial pressure. Therefore, parasympathetic activity is impaired in hypertensive rats, and vagal dysfunction could subsequently result in the downregulation of the α7nAChR.

Chronic hypertension is often accompanied by organ hypertrophy and inflammatory lesions [34,35]. To test whether α7nAChR dysfunction is associated with hypertensive EOD, the role of α7nAChR in inflammation and that of EOD in renovascular hypertension using α7nAChR knockout mice were investigated. After the induction of two-kidney, one-clip (2K1C) hypertension, α7nAChR knockout mice developed higher serum levels of pro-inflammatory cytokines and more severe EOD than the wild-type mice. This result shows that α7nAChR exerts an anti-inflammatory effect on 2K1C hypertension. The pharmacological rescue of the deficit in α7nAChR signaling in SHRs with PNU282987, a selective α7nAChR agonist, lowers pro-inflammatory cytokine levels and prevents NF-кB activation. Therefore, α7nAChR dysfunction contributes to EOD in multiple forms of hypertension through the disinhibition of pro-inflammatory cascades. This pathway represents a new target for the prevention of cardiovascular diseases secondary to hypertension.

Cholinergic anti-inflammatory pathway and myocardial infarction

Acute myocardial infarction is a major cause of mortality worldwide. Restoring myocardial perfusion with percutaneous coronary intervention after acute myocardial infarction is generally believed to be the most effective treatment strategy. However, reperfusion of ischemic tissues can stimulate the overproduction of pro-inflammatory cytokines. Recent findings demonstrated that VNS can decrease the level of TNFα in the serum, heart, and liver in a rat model of aortic occlusion [36]. Moreover, VNS can reduce the high incidence of severe arrhythmias and lethality and inhibit the increase in free radical blood levels and left-ventricle histologic alterations in a rat myocardial ischemia/reperfusion model [37]. These studies demonstrate that activation of the cholinergic anti-inflammatory pathway may be developed as a novel approach to managing ischemic heart disease.

Recent studies suggested that a lowered ABR function results in a poor outcome after myocardial infarction [38,39]. In a decades-long investigation of the relationship between myocardial infarction and ABR, research teams led by Schwartz and La Rovere [40-42] reported some important findings in both human and animal subjects. In 1988, a significantly increased mortality (40%) in myocardial infarction patients with depressed BRS relative to that in patients with normal BRS (2.9%) was reported. They also showed that increasing the BRS through physical exercise can improve the prognosis of myocardial infarction [43-45]. Increased input from cardiac sympathetic afferents following myocardial infarction inhibits ABR via the central AT1 receptor [46]. Augmented afferent input from sensory receptors in the left ventricle via the sympathetic afferent fibers also contributes to depressed BRS following myocardial infarction. Regional differentiation of the left ventricle through the interruption of afferent input emanating from cardiac sensory receptors and/or neural fibers in the ischemic region can increase BRS following myocardial infarction [47]. Impaired ABR, or more specifically, decreased vagal and increased sympathetic activities, can increase the risk of post-myocardial infarction death from cardiac causes.

Inflammation is very important in the development and prognosis of myocardial infarction. ABR dysfunction promotes the infiltration of inflammatory cells to the myocardium in rats with myocardial infarction [48]. ABR dysfunction can attenuate the parasympathetic activity and inhibit the α7nAChR function. Recently, Yu et al. [49] found that atropine-induced tachycardia was blunted in SAD rats, and the expression of VAChT and α7nAChR in ischemic myocardium was also lower. Thus, parasympathetic activity is impaired in SAD rats, and vagal dysfunction may subsequently result in the downregulation of α7nAChR. VNS improves cardiac function and prolongs survival time after myocardial infarction in rats and human patients [50-52]. Kong et al. [53] reported that the protective effect of VNS against myocardial infarction is associated with decreased TNFα, as well as a decreased TNFR1⁄2 ratio, possibly via α7nAChR activation. α7nAChR activation not only inhibits inflammation, apoptosis, and oxidative stress, but also promotes angiogenesis. Recently, Yu et al. [49] showed that ABR dysfunction attenuates angiogenesis after ischemia via α7nAChR. Therefore, baroreflex enhancement can be explored as a therapeutic strategy for the treatment of myocardial infarction. These studies indicate that the prognosis of myocardial infarction is intimately linked to vagal activity via α7nAChR.

Conclusions

Inflammation plays a critical role in the pathogenesis of cardiovascular diseases. The cholinergic anti-inflammatory pathway is a mechanism by which the efferent vagus nerve modulates inflammation by targeting α7nAChR and represents promising targets for novel therapeutic interventions. However, major obstacles need to be addressed, and many questions, such as the extent of protection that VNS or α7nAChR agonists can offer and whether VNS or α7nAChR agonists can be combined with other treatments, need to be answered.

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