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Clinica Chimica Acta 413 (2012) 406–410
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Clinica Chimica Acta
journal homepage: www.elsevier.com/locate/clinchim
Invited critical review
Apelin in acute myocardial infarction and heart failure induced by ischemia
Agnieszka M. Tycinska ⁎, Anna Lisowska, Wlodzimierz J. Musial, Bozena Sobkowicz
Department of Cardiology, Medical University of Bialystok, Poland
a r t i c l e
i n f o
Article history:
Received 11 September 2011
Received in revised form 17 November 2011
Accepted 21 November 2011
Available online 25 November 2011
Keywords:
Apelin
AMI
Heart failure
a b s t r a c t
Apelin is a recently isolated novel endogenous ligand for the angiotensin-like 1 receptor (APJ). Initial experiments in animal models indicate that the cardiovascular system is the main target of the apelin–APJ system.
Apelin plays an opposite role to the renin-angiotensin-aldosterone system as a compensatory mechanism. It
is reduced in patients with heart failure, also of ischemic origin. However, only animal studies concern the
role of the apelin–APJ system in myocardial ischemia. Less is known about the function of this adipokine in
an acute phase of myocardial infarction in human. The apelin–APJ system could perhaps be involved in myocardial protection during acute myocardial ischemia. In the current review we have summarized recent data
concerning the role of apelin in acute myocardial infarction and heart failure induced by ischemia.
© 2011 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . .
Overview of apelin physiology and pathophysiology . . . .
Apelin expression in acute hypoxia and myocardial infarction
3.1.
Animal studies . . . . . . . . . . . . . . . . . .
3.2.
Human studies . . . . . . . . . . . . . . . . . .
4.
Apelin and ischemic heart failure . . . . . . . . . . . . .
4.1.
Animal studies . . . . . . . . . . . . . . . . . .
4.2.
Human studies . . . . . . . . . . . . . . . . . .
5.
Apelin as a therapeutic target in heart failure? . . . . . . .
6.
Conclusions . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
2. Overview of apelin physiology and pathophysiology
Apelin belongs to the adipokines − a term used to denote cytokines, growth factors, and other proteins produced and secreted by
adipocytes. These factors are also called adipocytokines [1]. This
does not imply that expression and production of such factors is restricted to adipocytes as most of these factors are also produced by
a variety of other cell types. The term often refers to leptin and adiponectin, which are secreted by the adipocytes of adipose tissue. A variety of other factors are also released by adipose tissue in vitro and in
vivo and these have been also termed collectively as adipokines or
adipocytokines (TNF-alpha, IL-6, leptin, omentin, visfatin, adipsin,
resistin, apelin, retinol binding protein rbp4) [2].
In 1993 O'Dowd et al. identified an endogenous ligand for the
angiotensin-like 1 receptor (APJ) [3]. This is a ligand for one of the
earliest, so called “orphan” G-protein-coupled receptors (GPCRs).
GPCRs represent the largest group of transmembrane proteins
responsible for transduction of a diverse array of extracellular
signals. Recent progress in genome research revealed a total of
about 300 GPCRs [4]. Approximately 140 of these novel GPCRs do
not bind any known endogenous ligand and are described as
“orphan” GPCRs. APJ receptor possesses the closest identity to the
angiotensin II type 1 (AT1) receptor ranging from 40% to 50% in the
hydrophobic transmembrane regions, but does not bind angiotensin
II. The putative endogenous ligand for the APJ receptor, apelin-36,
was isolated from bovine stomach extracts by measuring extracellular acidification in a Chinese hamster ovary cell line expressing the
human APJ receptor [5]. The apelin gene, located on the long arm of
the human X chromosome, encodes a 77 amino acid preproapelin,
⁎ Corresponding author at: Department of Cardiology, Medical University of Bialystok, ul. M. Sklodowskiej-Curie 24a , 15-276 Bialystok, Poland. Tel.: + 48 857468656;
fax: + 48 857468604.
E-mail address: [email protected] (A.M. Tycinska).
0009-8981/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.cca.2011.11.021
A.M. Tycinska et al. / Clinica Chimica Acta 413 (2012) 406–410
and it is widely expressed in various tissues and cell types [6], Fig. 1.
Apelin-36 is a 36-amino acid C-terminal fragment of the preproapelin
and was first characterized as endogenous APJ receptor ligand, but
several smaller C-terminal peptides were shown to be even more potent in activating APJ. Shorter synthetic C-terminal peptides consisting of 13 to 19 amino acids were found to exhibit significantly
higher activity than apelin-36 [5,7], whereas the most effective pyroglutamylated form is apelin-13 [5], Fig. 1.
Apelin−APJ system is expressed in the central nervous system
and periphery [8] with a role in the regulation of fluid and glucose homeostasis, feeding behavior, vessel formation, cell proliferation and
immunity [9], Fig. 2. In magnocellular neurons of the hypothalamus,
apelin is upregulated by dehydration through a mechanism that
may involve arginine vasopressin [10]. However, the evidence indicates that the cardiovascular system is the main target of apelin.
Based on some results, it can be anticipated that apelin, like angiotensin II, may have an important role in the regulation of cardiovascular
homeostasis [6]. Apelin is one of the most powerful endogenous positive inotropic substances [11], Fig. 2. In addition to the inotropic effects of apelin, several mechanisms have been described whereby
apelin regulates vascular tone and blood pressure. Intravenous injection of apelin lowers blood pressure by triggering the release of nitric
oxide from endothelial cells [12] and reduces water and sodium uptake in the kidneys by inhibiting vasopressin discharging [13]. Moreover it has diuretic properties [13]. Apelin plays a primary role in
counteracting angiotensin-induced vasoconstriction [14].
There is some animal data suggesting that the apelin−APJ system
might be an important regulator of vascular function in diabetes [15],
Fig. 2. Animal and human data suggest that apelin production is enhanced in obesity and could help to understand potential links between obesity and associated disorders such as inflammation and
insulin resistance [16,17]. In adipocytes, apelin gene expression is
inhibited in the fasting state and stimulated by refeeding possibly
through changes in the plasma concentrations of insulin and
counter-regulatory hormones [17].
Apelin is present in human plasma and myocardium. Apelin
mRNA levels increase in left ventricle in chronic heart failure due to
coronary heart disease and dilated cardiomyopathy [18]. Moreover,
apelin plasma levels are reported to increase especially in the early
stage of left ventricular dysfunction [19].
However, the majority of studies regarding apelin have been provided on animal models; little is known about its function in human.
The current review is devoted to the role of apelin in acute myocardial infarction and ischemic heart failure.
3. Apelin expression in acute hypoxia and myocardial infarction
3.1. Animal studies
The majority of experimental data regarding the role of apelin in
cardiovascular system has been conducted in rodents. Sparse studies
used other animals. Del Ry et al. have been used a wild boar (Sus
scrofa) model to establish its genoma sequence for apelin for future
applications of molecular biology studies [20]. While other
Fig. 1. Apelin synthesis and metabolism (based on Japp A.G. and co-workers).
407
Fig. 2. Physiological and pathophysiological apelin actions (based on Castan-Laurell I.
and co-workers).
researchers, on the canine model, have investigated the influence of
apelin on changes in intracellular sodium current, which may contribute to the apelin inotropic effects [21].
Regulation of the apelin–APJ pathway is altered by acute ischemic
injury. Ronkainen et al. for the first time have demonstrated that hypoxia regulates apelin gene expression and secretion in cardiac myocytes [22]. Hypoxic induction of apelin could be a part of the acute
response of the heart muscle to an impaired oxygen supply, such as
at the time of myocardial infarction. Myocardial gene expression as
well as secretion of apelin are activated by hypoxia via activation of
hypoxia-inducible factor-1 (HIF-1). This factor is also responsible for
regulation of expression of several hypoxia-inducible genes including
erythropoietin, adrenomedullin and heart-specific atrial natriuretic
peptide [23–25]. Sheikh et al. in the murine model investigated influence of heart failure induced by ischemia on apelin−APJ pathway expression in the heart muscle, lung and skeletal muscle [26]. The
authors found in vivo and in vitro experiments that apelin and APJ
are markedly upregulated following ischemia and hypoxia via HIF2α pathway. They were able to demonstrate that this effect is restricted particularly to the postarterial (capillary and venous) endothelium. Apelin and APJ mRNA expression progressively increased by
consecutive weeks following ischemic injury. Accordingly, apelin expression is upregulated in vivo within 24 h of myocardial infarction.
Endogenous cardiac apelin and APJ are increased in rats with ischemic heart failure 6 weeks postmyocardial infarction [27]. Moreover,
infusion of apelin-13 significantly enhanced myocardial function in
failing hearts. Thus, the total myocardial apelin and APJ receptor
levels increase in compensation for ischemic cardiomyopathy. It is
not clear whether the stimulus for this upregulation is ischemia or
the early onset of heart failure. In contrast, both apelin and APJ expression fell in a further rodent model of ischemic myocardial injury
caused by repeated isoprotenerol administration [28]. However, it
must be noted that this model produced extensive myocardial injury
and very severe heart failure associated with hypotension and grossly
elevated left ventricular end-diastolic pressure. Interestingly, while
cardiac APJ mRNA levels were markedly downregulated in these
rats, both tissue levels and overall apelin-binding capacity of APJ
within the heart were increased. This might reflect either more efficient posttranscriptional processing of APJ or diminished breakdown
of existing APJ receptors, with or without a contribution from enhanced receptor recycling. In myocardium with a limited oxygen supply, increased apelin expression could therefore serve as an adaptive
mechanism to maintain the contractile function of the heart. It has
been shown that overexpression of HIF-1α reduced infarct size and
limited the progression of infarct-induced cardiac failure in mouse
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A.M. Tycinska et al. / Clinica Chimica Acta 413 (2012) 406–410
[29]. Thus, as a consequence of being a HIF target gene, apelin might
well play a part in the early events protecting the heart against
hypoxia-induced damage raising the possibility of using apelin as a
therapeutic agent for ischemic heart failure patients. Kleinz et al.
have showed that in ischemic myocardium of isolated rat hearts apelin mRNA is upregulated, but returns back to baseline after reperfusion [30]. Therefore the authors have suggested that apelin or a
pharmacological agonist of APJ receptors could act as novel approaches for attenuating myocardial ischemia and reperfusion injury
in patients with coronary artery disease. Recent interesting experimental data have indicated that the expression of the apelin−APJ
pathway during differentiation of bone marrow mononuclear cells
(BMSCs) into cardiomyogenic cells may be an important mechanism
in regulation of myocardial regeneration and its functional recovery
after acute myocardial infarction [31].
Thus, increasing evidence from pre-clinical models has suggested
that apelin−APJ signaling mediates important effects on hypoxia
and ischemia. However, the data provided with human studies
seem to be limited.
3.2. Human studies
Studies concerning the role of apelin in AMI in humans are spare.
In humans the majority of studies have been conducted in vivo. However, Pitkin et al. have performed an investigation on human tissues
(cardiomyocytes as well as coronary artery and epicardial adipose tissues), which were collected were from patients undergoing cardiac
transplantation for dilation cardiomyopathy or ischemic heart disease, or from control hearts from donors where there was no suitable
recipient [32]. They have found changes in the apelin/APJ system in
human diseased cardiac and vascular tissue. Apelin was upregulated in human atherosclerotic coronary arteries and potently
constricted vessels. On the other hand, they found the decrease in
APJ receptor density in heart failure, which may limit the positive inotropic actions of apelin, contributing to contractile dysfunction. In
vitro model was also used to discover that apelin is a novel insulinregulating islet peptide in humans as well as several laboratory animals [33].
It is known that exogenous apelin has acute and chronic positive
inotropic effects in the myocardium [11,34,35]. In man in vivo it has
been shown that acute apelin administration causes NO-mediated arterial vasodilation, but does not appear to affect peripheral venous
tone [36]. Our previous studies provided information that in low
risk ST-elevation myocardial infarction patients, treated with primary
percutaneous coronary intervention (pPCI) and with preserved left
ventricle ejection fraction (LVEF) the decrease of plasma apelin concentrations could be found in the first five days after the onset of
myocardial infarction [37]. This reduction was independent of the degree of LV dysfunction and prognosis [38]. Weir at al. in patients with
acute myocardial infarction (AMI) and low LVEF confirmed our results: plasma apelin concentration was lower in patients with AMI
in comparison with the control group early after infarction and persisted low over time [39]. Apelin concentration did not correlate
with any parameter of LV. Interesting results were brought by Kadoglou et al. [40]. A total of 355 participants were enrolled into the
KOZANI Study. Among them there were 80 patients with unstable angina (UA) and 115 patients with acute myocardial infarction (AMI)
hospitalized in the coronary care unit. Apelin concentrations were
lower in coronary artery disease (CAD) patients as compared to controls. UA and AMI groups had lower apelin levels on admission compared with the asymptomatic CAD group. Moreover, apelin
concentrations were inversely associated with the severity and the
acute phase of CAD, which suggests its involvement in the progression and destabilization of coronary atherosclerotic plaques. Similar
results were obtained by Li et al. [41]. Reduced apelin levels were observed in this homogenous population of stable angina subjects and
the plasma apelin level was negatively correlated with the degree of
coronary stenosis as measured by Gensini score.
4. Apelin and ischemic heart failure
4.1. Animal studies
The role of apelin−APJ in the pathogenesis of heart failure has received a great attention. Szokodi et al. were the first group to report
downregulation of apelin mRNA in cardiac myocytes under cyclic
stretch in vitro and in ventricular myocardium from two rat models
of hypertensive heart failure [11]. In animal models of heart failure
the expression of apelin and APJ is increased or maintained in animals
with left ventricular hypertrophy and compensated heart failure, but
downregulated in those with severe, decompensated heart failure.
This could be due to cardiac dilatation in advanced heart failure,
which may contribute to downregulation of the apelin–APJ system
since cardiomyocytes subjected to mechanical stretch in vitro exhibit
markedly reduced expression [11]. In ischemic heart failure, however,
the role of apelin−APJ is less clear. Both upregulation and downregulation of the apelin−APJ receptor system have been reported [27,28].
The cardiac apelin system is regulated by the angiotensin II–angiotensin type 1 receptor system directly. The cardiovascular effects of apelin are not mediated by the angiotensin II type 1 receptor [42],
however, the inhibition of the renin–angiotensin system have beneficial effects, at least in part, through restoration of the cardiac apelin
system in the treatment of HF [43].
To estimate the influence of apelin on infarct size, some animal
studies based on ischemia/reperfusion model have been conducted.
It was shown that apelin enhanced by ischemia/reperfusion injury,
improves cardiac dysfunction by suppressing myocardial apoptosis
and resisting oxidation effects [44]. In another ischemia/reperfusion
rat model, apelin-13 reduced infarct size and limited the postischemic
myocardial contracture [45].
4.2. Human studies
The findings from preclinical models could be translated into
human studies. Apelin–APJ expression is altered in patients with
chronic heart failure (CHF). Initial reports suggested that plasma apelin concentrations were mildly elevated in the early stages of heart
failure, but fell with more advanced disease [18,19]. In patients with
severe CHF, the improvement in New York Heart Association
(NYHA) symptoms class and LVEF following cardiac resynchronisation therapy together with the increase of plasma apelin concentration were found [46]. Therefore, current data strongly suggest that
apelin expression is at least maintained and possibly augmented in
mild, compensated heart failure, but declines with advancing disease.
Moreover, apelin plasma levels are reported to increase especially in
the early stage of left ventricular dysfunction [19]. Upregulation of
apelin mRNA was observed in myocardium from ischemic heart failure patients [18], and downregulation of apelin mRNA in myocardial
injury [28]. Such equivocal findings might stem from the different
time points post-infarction at which apelin expression was measured
or might be the result of differences in heart failure severity leading to
the concomitant activation of other interfering pathways. In order to
further elucidate the role of apelin−APJ in ischemic heart failure, it is
therefore important to know how the apelin receptor system in the
heart responds to an ischemic insult independently of all other
factors.
Interesting findings have been found by Földes et al. [18]. They
compared circulating plasma apelin levels to the tissue apelin-like
immunoreactivity expression in patients with heart failure and
healthy men. Apelin was found to be present in normal human plasma. However, plasma levels of apelin were significantly decreased
in patients with heart failure (III NYHA class) due to coronary heart
A.M. Tycinska et al. / Clinica Chimica Acta 413 (2012) 406–410
disease compared to normal subjects. On the other hand, left ventricular apelin mRNA levels were significantly increased in patients with
heart failure due to coronary heart disease or idiopathic dilated cardiomyopathy. Although left ventricular apelin levels tended to be
higher in patients with coronary heart disease and idiopathic dilated
cardiomyopathy, these changes were not statistically significant.
Apelin-like immunoreactivity expression was 200-fold higher in atrial tissue than ventricular tissue and correlated well with plasma apelin concentrations suggesting it may be the major source of
circulating apelin. The changes in atrial and ventricular mRNA and
peptide levels of apelin observed in the present study resembled
those of ANP [47]. Thus, the induction of apelin gene expression in
the failing ventricles, similar to ANP, constitutes an adaptive mechanism triggered by increased cardiac overload.
However, recent data have produced conflicting findings. Chong et
al. reported that plasma apelin concentrations are decreased in patients with severe CHF. About 50% of the investigated patients had
CHF due to ischemic heart disease and the majority of them displayed
severe heart failure (73% were at NYHA class III or IV, and the mean
ejection fraction was 15%) [48]. Goetze et al. have demonstrated
that plasma apelin concentrations were decreased in patients with
decreased LVEF (median 20%) due to CHF of mixed etiology, but
even more in patients with parenchymal lung disease and idiopathic
pulmonary hypertension and preserved left ventricle ejection fraction
(median LVEF 65% and 60%, respectively) [49]. In patients with idiopathic dilated cardiomyopathy (LVEF b45%) plasma apelin levels
were similar as compared to healthy control subjects [50]. The discrepancy of these results may be largely caused by the differences
in study populations.
5. Apelin as a therapeutic target in heart failure?
Japp and co-workers were the first to demonstrate an influence of
acute administration of apelin-36 infusion on human cardiovascular
system in vivo [51]. Apelin was injected into peripheral artery as
well as intracoronary bolus was given in order to measure coronary
blood flow and LV contractility and pressures. Intravenous infusion
of apelin was given for the systemic hemodynamic study. They were
able to demonstrate peripheral and coronary vasodilatation, improvement of myocardial contractility, reduction of LV pressures and rise in
cardiac output. Hemodynamic results during apelin infusion were
similar in healthy volunteers as well as in patients with coronary artery disease and heart failure. Thus apelin may become a very interesting therapeutic agent in patients with severe heart failure. From
the other experiments it is known that, in contrast to another inotropic agents, long time apelin administration does not induce LV hyperthrophy, moreover, by simultaneous reduction of loading condition
and cardiac work oxygen demand is diminished [51].
Summarizing, there is still a way to establish apelin as a therapeutic agent for heart failure, especially chronic heart failure. The long
term effect of apelin and the direct effect of apelin in stimulating
the heart cells are still not well studied.
6. Conclusions
In summary, available data from animal and human studies suggest that apelin–APJ system is:
1. upregulated in response to hypoxia/ischemia
2. maintained or augmented in chronic pressure overload and the
early stages of heart failure
3. essentially downregulated in severe heart failure.
The studies confirm the validity of apelin as a new adipokine of
cardiovascular importance. Still available data do not give responses
to all questions. Existing studies provide sparse data. Experimental
and clinical investigations performed both in vivo and in vitro on
409
various populations do not clarify the real significance of apelin.
What is the exact diagnostic and prognostic role of apelin in AMI patients? Is apelin a goal for treatment in AMI or a new substance for the
treatment in patients with heart failure especially of ischemic origin?
Thus, there is a need to perform a prospective study with a homogenous population to answer the above doubts.
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