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European Journal of Heart Failure 2008 10(8):725-732; doi:10.1016/j.ejheart.2008.06.002
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© 2008 European Society of Cardiology

The role of apelin in cardiovascular function and heart failure

Badrinathan Chandrasekaran*, Owais Dar and Theresa McDonagh

Imperial college, Royal Brompton Hospital campus Sydney St, London SW3 6NP, United Kingdom

* Corresponding author. Tel.: +44 2073588121x8178. E-mail address: b.chandrasekaran{at}ic.ac.uk (B. Chandrasekaran).


   Abstract
Top
 Abstract
1. Introduction
 2. Background
 3. The role of...
 4. The apelin-APJ system...
 5. Cardiovascular development...
 6. Other physiological actions...
 7. Conclusions
 References
 
Apelin is a novel peptide that acts through the APJ receptor, sharing similarities with the angiotensin II–angiotensin II type 1 receptor pathway. It is a peripheral vasodilator, powerful inotrope and may affect central fluid homeostasis. Animal and human studies suggest that it may play a role in the pathogenesis of heart failure by modulating the harmful effects of angiotensin II. Apelin is reduced in patients with heart failure and up regulated following favourable left ventricular remodelling. It is widely distributed in a number of tissues, mainly restricted to vascular endothelium. This comprehensive review of the literature highlights the important studies that have led to the discovery of apelin and its role in cardiovascular function and heart failure.

Key Words: Apelin • APJ • Heart failure

Received November 30, 2007; Revised April 21, 2008; Accepted June 4, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Background
 3. The role of...
 4. The apelin-APJ system...
 5. Cardiovascular development...
 6. Other physiological actions...
 7. Conclusions
 References
 
Apelin is an endogenous peptide that is a ligand for the angiotensin-like 1 (APJ) receptor [1,2]. The apelin-APJ genes are ubiquitously expressed throughout a number of tissues and show similarities with the angiotensin II (Ang II)-angiotensin II type 1 (AT1) receptor distribution [3]. Initial experiments in animal models indicate that the apelin-APJ system has a role to play in cardiovascular homeostasis. Apelin is a powerful inotrope, peripheral vasodilator and may be involved in fluid homeostasis, making it an attractive target for heart failure therapy. The proposed effects of the apelin-APJ system are opposite to the effects of the Ang II-AT1 pathway, which makes it an interesting area for research into the mechanisms of heart failure as well as opening up new targets for treatment. This comprehensive review identifies the key studies that have investigated the function of the apelin-APJ system in the cardiovascular system and its role in the pathogenesis of heart failure.


   2. Background
Top
 Abstract
 1. Introduction
 2. Background
3. The role of...
 4. The apelin-APJ system...
 5. Cardiovascular development...
 6. Other physiological actions...
 7. Conclusions
 References
 
2.1. History
In 1992, a gene for a receptor with marked similarities to the AT1 receptor was identified. At that time there was no known ligand and it was named the APJ receptor (also known as the Angiotensin-like 1 receptor) [1]. The APJ receptor is a 377 amino acid, 7 transmembrane domain, G-coupled receptor whose gene is located on the long arm of chromosome 11 [1]. Angiotensin II (Ang II) is unable to activate the APJ receptor despite its similarities to the AT1 receptor, and in the absence of a ligand it was known as an "orphan" receptor until 1998 when apelin was isolated from bovine stomach extracts [2]. Apelin is secreted as a 77 amino acid pre-proprotein which is cleaved to form several active peptides denoted by their length as apelin-13, -16, -17, -19 and -36 [2,4,5]. It has been shown that apelin-13 and apelin-17 exhibit much stronger activity than apelin-36 [2]. These isoforms are comprised of C-terminal fragments, which may be responsible for the receptor binding and biological activity of apelin [6]. There is no evidence to date that the apelin-APJ pathway involves more than one receptor.

2.2. Distribution of apelin-APJ system
Apelin and APJ messenger RNA (mRNA) is expressed extensively in body tissue. There are particularly high concentrations in the cerebellum, vascular endothelium, heart, lung and kidney [2-5,7-11]. It is currently thought that the apelin-APJ pathway is capable of juxtacrine, paracrine and autocrine signalling. There are high concentrations of APJ receptors in the heart and it is expressed on a number of cell types including endothelium, smooth muscle and the myocyte [12]. APJ receptors are expressed in the heart at a similar density to ATI receptors and using radioligand-binding assays human heart tissue demonstrated a high binding affinity for apelin [3]. Apelin immunoreactivity is found in endothelial cells of human cardiac and vascular tissue but not in other tissues, suggesting that the physiological effects of apelin may be mediated by its actions on the endothelium [13].


   3. The role of apelin in the cardiovascular system
Top
 Abstract
 1. Introduction
 2. Background
 3. The role of...
4. The apelin-APJ system...
 5. Cardiovascular development...
 6. Other physiological actions...
 7. Conclusions
 References
 
3.1. Physiological actions
The role of the apelin-APJ system in cardiovascular physiology and its interaction with other neuroendocrine pathways has not been fully elucidated. However, the small number of reported studies, which have been performed predominantly in animals, indicate that apelin signalling may be involved in the regulation of vascular tone, cardiac contractile function and fluid balance.

3.2. Vascular tone
Physiological experiments in anaesthetised and conscious animal models have yielded conflicting results about the role of apelin in regulating vascular tone. In anaesthetised rats, intravenous apelin resulted in a transient drop in systolic and diastolic blood pressure with no change in heart rate [3,11]. The magnitude of blood pressure reduction was dose dependent, inversely correlated with molecular size and abrogated following pre-treatment with a nitric oxide synthase inhibitor [11]. In conscious rodents, apelin is a venous and arterial dilator in vivo and also causes a mild tachycardia that is abolished by ganglionic blockade [14]. These initial experiments suggest that apelin is a peripheral vasodilator whose effects may be mediated by a nitric oxide (NO) dependent mechanism and that the changes in heart rate are secondary to a baroreceptor reflex as opposed to a direct chronotropic effect. However, experiments in conscious sheep and both anaesthetised and conscious rats have shown the opposite effect, with an increase in mean arterial blood pressure and heart rate [15-17]. In a large animal model, intravenous apelin-13 caused a biphasic response in mean arterial blood pressure and cardiac output, with an initial fall followed by a subsequent rise and then a return to baseline over 15 min. Right atrial pressure was increased and there was a parallel increase in natriuretic peptides [15]. These results are difficult to interpret because of differences in methodology and the different doses of apelin administered.

In vitro experiments have highlighted mechanisms by which apelin can act as a vasodilator or vasoconstrictor. In isolated rat aortas the mechanism of arterial vasodilatation mediated by apelin, was shown to involve the L-arginine/nitric oxide synthase (NOS)/nitric oxide pathways [18]. APJ is expressed in the vascular smooth muscle of rats where apelin induces phosphorylation of the myosin light chains [19] and in human saphenous veins where it causes vasoconstriction in the absence of a functional endothelium [20]. This suggests that the predominant actions of apelin on peripheral vascular tissue are mediated by NO production from the endothelium.

The effects of apelin on vascular tone in vivo may be dependent on a dynamic interaction between the apelin-APJ system and Ang II-ATI. In spontaneously hypertensive rats, all trans retinoic acid (atRA) which up regulates g-protein receptor signalling, reduced blood pressure, increased APJ and apelin expression in the aorta [21]. This was accompanied by an increase in NO and a reduction in AT1 expression. Apelin did not directly affect the tone in rat portal veins; however, regardless of the presence of endothelium, apelin abrogated the vasoconstrictor response to Ang II by a NO dependent mechanism [22]. In APJ knock-out mice, baseline blood pressure was no different compared to the wild type, however the knock-out mice showed an increased vasopressor response to Ang II [23]. In disease states, an alteration in the normal interaction between apelin and Ang II may contribute to vascular disease. In the aortas of diabetic mice there is reduced expression of APJ, an enhanced contractile response to Ang II and reduced relaxation with acetylcholine. This abnormal vascular response was modified by pre-treatment with apelin [24].

The difficulties associated with unravelling the role of apelin in the modulation of vascular tone are compounded by its possible effects on the central regulation of blood pressure; an effect which may be greater than its peripheral effects [16,17]. The actions of apelin may also be dependent on fragment size and the type and location of the vascular bed upon which it is acting.

3.3. Contractile actions
Apelin has a powerful dose dependent inotropic effect on isolated animal preparations and in intact animals [25-27]. An infusion of apelin in isolated perfused rat hearts paced at a constant rate and contracting volumetrically, produced a positive inotropic response and increased the peak rate of left ventricular pressure rise (peak dP/dT) [27]. Pressure volume measurements in rats and mice demonstrated similar findings in vivo [25,26,28]. In vivo, chronic apelin increased the velocity of circumferential shortening and cardiac output in conscious normal mice as demonstrated by echocardiography, without causing ventricular hypertrophy [25]. In the failing heart after experimental infarction, apelin infusion also resulted in an improvement in cardiac contractility making its role in the treatment of heart failure an interesting possibility [26]. The inotropic effects of apelin are not affected by inhibition of nitric oxide synthase, antagonism of adrenergic signalling or blockade of endothelin receptors nor are they dependent on cardiac innervation [27]. Apelin is thought to exert its inotropic action by increasing the availability of intracellular calcium rather than enhancing the calcium sensitivity of the myofilaments [27,29]. This increase in contractility may be even more potent in the failing myocardium [29]. It is not known how calcium availability is increased, although phospholipase C (PLC), protein kinase C (PKC), sarcolemmal-H + and Na+-Ca 2+ exchangers have been shown to be involved [27] (Fig. 1). The pleiotropy of actions of APJ receptor signalling mean further studies are needed to clarify the exact mechanisms by which apelin increases contractility.


Figure 01
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  		Fig. 1 Proposed actions of apelin in cardiac muscle contraction. Calcium enters the cell via L-type calcium channels (L-Ca2+) and initiates calcium release from the sarcoplasmic reticulum (SR) by activating the ryanodine receptor (RyR). This massive Ca2+ release is required to trigger the contractile process. Calcium reuptake is mediated by the energy requiring sarcoendoplasmic reticulum Ca2+- adenosine triphosphatase (SERCA2A) and Phospholamban (P) which in turn allows relaxation. Apelin activates protein kinase C (PKC) and phospholipase C (PLC) that acts on the sarcolemmal, Na+-H+ exchanger (NHE) to increase intracellular Na+ resulting in an increase in intracellular Ca2+ by action of the reverse mode Na+ -Ca2+ exchanger (NCX). This leads to an increase in available cytosolic calcium for the cardiac contractile apparatus [27].

 
3.4. Role in fluid balance
The role of apelin in fluid homeostasis is unclear. There is conflicting data from animal work concerning the actions of apelin on antidiuretic hormone (ADH). Apelin and APJ are expressed in the supraoptic and paraventricular areas of the hypothalamus, areas which play a vital role in fluid balance via production of ADH [9,30]. Apelin is also found in neurons that also express ADH mRNA, suggesting that it may have an antidiuretic action by inhibiting ADH release [31-33]. However, functional studies on animals have yielded different results, with intracerebral infusions of apelin in rats initially showing decreases in circulating ADH with a reduction in dehydration induced water intake [34,35]. These findings were contradicted by subsequent studies involving both peritoneal and intracerebral infusions of apelin [36,37]. Furthermore in APJ and apelin knock-out mice, water intake and urinary electrolyte concentrations were no different to wild type mice exposed to the same conditions [23,38].

Although these studies raise interesting questions about the role of the apelin-APJ system in cardiovascular homeostasis and fluid balance, further studies are needed to clarify the overall effect of apelin on cardiovascular physiology at a local and central level.


   4. The apelin-APJ system in cardiovascular disease
Top
 Abstract
 1. Introduction
 2. Background
 3. The role of...
 4. The apelin-APJ system...
5. Cardiovascular development...
 6. Other physiological actions...
 7. Conclusions
 References
 
The proposed cardiovascular effects of the apelin-APJ system are opposite to the effects of the renin-angiotensin system (RAS), which is known to play a vital role in the pathogenesis of heart failure [39]. Therefore, the apelin-APJ axis may act as a compensatory mechanism initially ameliorating the harmful effects of ATI activation, but becoming down regulated in end end-stage heart failure. The carboxypeptidase angiotensin converting enzyme (ACE) II which breaks down Ang II into Ang [1-7] also acts on apelin 36 and apelin 13, suggesting that there is a dynamic interaction between the apelin and Ang II pathways [40]. There have been a number of clinical studies in animals and humans that go some way towards supporting this hypothesis.

4.1. Animal models of heart failure
Apelin mRNA was markedly down regulated in cultured rat myocytes subjected to mechanical stretch and two different rat models of chronic ventricular pressure overload [27]. In an ischaemic heart failure model, apelin infusion increased stroke volume and cardiac contractility in rats and controls [26,28]. In isoproterenol induced myocardial injury in rats, apelin and APJ genes were down regulated and apelin infusion ameliorated the effects of cardiac injury [41]. However, a more recent study has suggested that the direct inotropic effects of apelin may only be transitory in the absence of mechanical loading [42]. In compensated ventricular hypertrophy myocardial apelin and APJ mRNA is initially preserved and only down regulated when the Dahl salt sensitive rats undergo transition to ventricular failure [43]. Interestingly, only treatment with an Ang II receptor blocker restored apelin-APJ concentrations and infusion of Ang II resulted in decreases in apelin and APJ within 24 h. However, the other treatment arms also restored cardiac function without up regulating apelin and APJ levels. Exercise training in spontaneously hypertensive rats reversed the pathological consequences of sustained hypertension by up regulation of apelin and APJ in the myocardial and vascular tissue with an increase in plasma apelin [44]. This suggests that the benefits of RAS inhibition may in part be mediated by an up regulation in the apelin-APJ system. Apelin deficient mice developed contractile dysfunction with age and with pressure overload [38], suggesting that apelin may maintain cardiac contractility in the presence of sustained pressure overload. However, the findings in apelin knock-out mice are different to the APJ deficient mice in which the only abnormality was an increased blood pressure response to angiotensin II infusion under conditions of ACE inhibition or mutant AT1 receptor background [23].

4.2. Apelin in myocardial ischaemia
In acute ischaemic myocardial injury, apelin may have a protective role. In vitro and vivo studies have demonstrated that, like adrenomedullin, apelin and APJ gene expression is up regulated in response to hypoxia in peripheral and cardiac tissue [45,46]. Following experimental myocardial infarction in rats an increase in apelin and APJ expression was observed [28]. Subsequent exogenous apelin infusion improved cardiac contractility, suggesting that the endogenous apelin production was insufficient to activate all the APJ receptors. Therefore, the apelin-APJ system may be induced in ischaemia to limit myocardial injury. A more recent study provides insight into a possible mechanism whereby the apelin-APJ system may protect the myocardium form ischaemia reperfusion injury by its actions on the reperfusion injury salvage kinase (RISK) pathway [47,48].

4.3. Apelin in human ventricular dysfunction
In humans apelin like immunoreactivity was reduced in patients with left ventricular dysfunction secondary to ischaemic heart disease [49]. However, ventricular apelin mRNA was significantly increased in patients with dilated cardiomyopathy and heart failure secondary to ischaemic heart disease. APJ receptor mRNA was also reduced in patients with dilated cardiomyopathy in this study, suggesting that abnormalities in the apelin apelin-APJ pathway may play some part in the pathogenesis of heart failure in humans.

Plasma concentrations of apelin in patients with chronic heart failure are reduced compared to normal controls [50]. Although smaller studies have suggested that initially apelin is raised in mildly symptomatic heart failure and reduced in more symptomatic patients, this was not confirmed in a larger case series, which showed no significant differences between functional classes or relationship with ejection fraction [50,51]. In patients with dilated cardiomyopathy APJ polymorphisms were not found in a greater frequency compared with normal healthy controls. However, those individuals with at least one copy of the APJ 212A allele were less likely to have progression of heart failure over a 37 month follow up [52]. This study suggests that it is unlikely that defects in the APJ receptor gene caused dilated cardiomyopathy however they may affect the rate of progression to symptomatic heart failure.

In end end-stage heart failure patients who had left ventricular assist devices and successful left ventricular reverse remodelling, tissue concentrations of apelin were increased and the APJ gene was up regulated [51]. In one study, plasma apelin was increased in patients undergoing cardiac resynchronisation therapy (CRT) after a mean follow up of 9 months [53]. All the patients experienced clinical improvement following CRT and all but one had significant reverse remodelling. In the one patient who did not successfully remodel, the apelin concentration was still increased.

Although there are some conflicting data on the exact role of the apelin-APJ system in the pathogenesis of human heart failure, these early studies suggest that the apelin-APJ axis is down regulated in heart failure and up regulated with favourable left ventricular remodelling (Fig. 2). Whether the primary source of this apelin is the cardiac tissue or peripheral tissue is not known. The interactions of the apelin-APJ system with other neurohormonal systems involved in the pathogenesis of heart failure are not known and the effect of disease modifying therapies such as ACE-I and beta-blockers on apelin concentrations has not been investigated.


Figure 02
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  		Fig. 2 The role of apelin in heart failure. Ang II = Angiotensin II AT1 = angiotensin-II type one receptor. NO = nitric oxide.

 
4.4. The use of apelin as a biomarker in human heart failure
There have only been three studies that have compared the use of apelin and other biomarkers to aid in the diagnosis of heart failure. In one study, apelin-36 was reduced in patients with chronic pulmonary disease and normal cardiac function while BNP concentrations remained unchanged [54]. However, in patients with severe left ventricular dysfunction or idiopathic pulmonary hypertension apelin was still decreased but BNP was raised suggesting that apelin may be a marker for chronic pulmonary disease. In patients presenting to an emergency room with dyspnoea, apelin did not reliably predict acute heart failure and was not a prognostic marker in those with confirmed heart failure [55]. In patients with chronic heart failure secondary to idiopathic dilated cardiomyopathy, plasma apelin was no different to normal controls unlike the other biomarkers which included NT-proBNP, IL-6, TNF-{alpha} and norepinepherine [56]. Unlike the biomarker BNP, which can be used as a diagnostic screening test and prognostic marker for heart failure, current data does not suggest a similar application for apelin.

4.5. Apelin in atherosclerosis
There is a small amount of evidence that the apelin-APJ system may be involved in modulating endothelial oxidative stress and the formation of coronary atherosclerotic plaques. In APJ and ApoE double knock-out mice fed a high cholesterol diet, atherosclerotic plaque burden was considerably reduced compared with single ApoE knock-out mice without any difference in cholesterol concentrations [57]. There was also a reduction in markers of oxidative stress and vascular smooth muscle cells in the double knock-out mice. However, in humans with hypercholesterolaemia, plasma apelin was decreased compared to matched controls [58] and there was no increase in the expression of APJ receptors in atherosclerotic vessels compared to normal controls [59].

4.6. Apelin and cardiac conduction
Apelin may well have an important role to play in cardiac electrophysiology. A recent study has shown that high concentrations of apelin are found around the intercalating discs that are vital to cellular electrical coupling [42]. In this study apelin increased the frequency of spontaneous activation, conduction velocity and reduced the field potential duration in monolayers of cultured neonatal rat cardiomyocytes. In a large animal model there was evidence of high grade AV block in 50%, which was not observed in smaller animals raising concerns about the use of supraphysiological doses of apelin for therapy [15]. Apelin levels have been shown to be raised in patients without structural heart disease and in sinus rhythm, who have a history of lone atrial fibrillation [60]. However, the true significance of this finding and the relationship between medication usage and timing of previous cardioversion require further investigation, therefore the role of apelin in human arrhythmogenesis is unknown.

4.7. Apelin and the cardiorenal axis
Heart failure and renal failure are inextricably intertwined giving rise to the term "cardiorenal syndrome". The actions of the RAS directly affect the kidney and therefore a link between renal disease and the apelin-APJ system seems entirely plausible. In haemodialysed patients without heart failure symptoms, the concentration of apelin-36 was lower in patients with coexisting coronary artery disease and correlated with diastolic LV dimensions [61]. In another study by a different group, apelin was found to be lower in dialysed uraemic patients, most of whom had systolic dysfunction, compared to patients with dilated cardiomyopathy (DCM) with normal renal function [62]. This observation was independent of cardiac function despite the DCM patients having lower ejection fractions. Apelin has also been shown to regulate renal arterial tone in diabetic mice by modulating the vascular responsiveness to Ang II and by increasing generation of NO by endothelial NOS [63]. It is well documented that cardiovascular disease is a major cause of mortality and morbidity in patients with end-stage renal disease. Although further work is needed, there may well be a link between the apelin-APJ system and the pathogenesis of cardiovascular disease in chronic renal disease, which opens up the possibility of apelin as a therapeutic agent in these patients.


   5. Cardiovascular development and angiogenesis
Top
 Abstract
 1. Introduction
 2. Background
 3. The role of...
 4. The apelin-APJ system...
 5. Cardiovascular development...
6. Other physiological actions...
 7. Conclusions
 References
 
There is growing evidence that apelin and APJ may play an important role in cardiac development and angiogenesis. In zebrafish, apelin and its receptor have been shown to control heart field formation during gastrulation and to regulate the migration of early myocardial progenitors [64]. Under or over expression of apelin-APJ signalling results in a reduction in cardiomyocyte numbers and abnormal cardiac morphology [65]. Similar findings have also been shown in the frog embryo [66]. Apelin and APJ are also expressed in the developing vasculature and in other endothelial structures in the zebrafish and in the frog [67,68]. In retinal cell lines, apelin induces angiogenesis [69]. However, it is not known whether apelin has a similar role to play in vivo.

Despite these findings, APJ and apelin deficient mice do not show any abnormalities in cardiovascular morphological development [23,38]. The reason for the differences between the findings in APJ deficient mice and the zebrafish and frog models is not known, but may be due to the presence of different signalling mechanisms involved in cardiac differentiation in mice.


   6. Other physiological actions of apelin
Top
 Abstract
 1. Introduction
 2. Background
 3. The role of...
 4. The apelin-APJ system...
 5. Cardiovascular development...
 6. Other physiological actions...
7. Conclusions
 References
 
The extensive distribution of apelin means that it is likely to have a wide range of effects on a variety of different organs. Most of these are beyond the scope of this review but are summarised briefly as follows.

Apelin is one of a number of adipokinins (adiponectin, leptin, resistin), abundantly expressed in adipose tissue and up regulated by insulin and steroids [70]. The high concentration of apelin and its receptor in the anterior pituitary also point towards a role in the adrenal neurohormonal axis [71,72]. Apelin may also be involved in immune signalling and has been shown to influence T-cell cholinergic activity in human cell lines and cytokine production in mice [73,74]. Apelin also inhibits HIV-1 viral entry into CD4+ cells by preventing the virus binding to APJ, which acts as a co receptor for HIV1 [75,76].


   7. Conclusions
Top
 Abstract
 1. Introduction
 2. Background
 3. The role of...
 4. The apelin-APJ system...
 5. Cardiovascular development...
 6. Other physiological actions...
 7. Conclusions
References
 
The discovery of the apelin-APJ axis is an exciting development in cardiovascular research. Although the exact mechanisms of how this molecular pathway interacts with the Ang II-AT1 pathway are still to be fully elucidated, there is growing evidence that apelin may be involved in the transition from compensated hypertrophy to clinically significant heart failure. The use of apelin as a diagnostic or prognostic marker in human heart failure seems unlikely on the basis of current evidence. The vasodilator and inotropic actions of apelin, in addition to its up regulation after favourable left ventricular remodelling, open up the possibility of its use as a therapeutic agent in heart failure. Apelin is abundantly present in endothelial tissue in a number of organs and it is still not known whether the increases in plasma concentrations following favourable left ventricular remodelling occur as a result of increased myocardial apelin production or enhanced peripheral production following improvement in central haemodynamics. The relative importance of the central and peripheral actions of apelin on normal cardiovascular physiology and cardiovascular disease is also undetermined. Apelin may also be involved in cardiac electrophysiology although its exact role in vivo is not known therefore any therapeutic application requires caution because of the risk of malignant ventricular arrhythmias or heart block. The discrepancies between initial experiments on embryos and the more recent knock-out mice models make it difficult to make firm conclusions about the role of the apelin-APJ system in cardiac development.

There are number of unanswered questions about apelin and its receptor APJ, therefore further research into the role of the apelin-APJ axis in normal cardiovascular physiology and in disease states, is now required.


   References
Top
 Abstract
 1. Introduction
 2. Background
 3. The role of...
 4. The apelin-APJ system...
 5. Cardiovascular development...
 6. Other physiological actions...
 7. Conclusions
 References
 

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