Apelin, an endogenous peptide, was identified as a ligand of the orphan G protein-coupled receptor APJ, so the name apelin comes from APJ Endogenous Ligand. Apelin was first isolated from the bovine stomach (Tatemoto et al., 1998). The APJ human gene (APLNR) encodes a seven-transmembrane protein closely related to the angiotensin receptor (O'Dowd et al., 1993). Both proteins share an identity of 54% in the transmembrane regions. However, angiotensin II does not bind to APJ (Lee et al., 2000). In addition to angiotensin II, apelin is also a substrate for catalytic angiotensin-converting enzyme 2 (ACE2) activity in vitro (Sato et al., 2013). The apelin receptor contains consensus sites for palmitoylation, glycosylation, and phosphorylation by cyclic adenosine monophosphate (cAMP)-dependent protein kinase (O'Dowd et al., 1993; Tatemoto et al., 1998). The apelin-encoding gene (APLN) is located on chromosome Xq25-26.1 (Lee et al., 2000) and encodes a 77-amino acid prepropeptide (Figure 1A). Preproapelin is cleaved from its C-terminus to produce a mature apelin peptide, apelin-36, or a family of shorter peptides (apelin-17,−12, and−13), the latter of which also exists as a pyroglutamyl form, [Pyr¹]apelin-13 (Habata et al., 1999) (Figure 1B).

In 1999, Habata et al. demonstrated the secretion of large amounts of apelin peptides into bovine colostrum and milk (Habata et al., 1999). Tissue expression analyses revealed, that the distribution of preproapelin and APJ mRNA were similar. The apelin peptide was detected in the spinal cord and several human brain regions (Matsumoto et al., 1996; Edinger et al., 1998; Lee et al., 2000). In rats, preproapelin and APJ mRNA were detected in brain and peripheral tissues, including testis, intestine, kidney, and in the fetus (Lee et al., 2000; O'Carroll et al., 2000). High level apelin mRNA levels were also identified in the rat heart (Lee et al., 2000), lung, and mammary glands (Kawamata et al., 2001), however only faint signals were detected in spleen and liver (Lee et al., 2000). Tissue expression of apelin-17 in humans was also determined using immunohistochemistry; apelin-17 is highly expressed in chondrocytes, endothelial cells, the heart, skin, brain, spleen, thymus, and lungs. An intermediate expression level of apelin was found in skeletal muscle. In the liver, pancreas, and kidney, apelin-17 was detected in relatively low levels (De Falco et al., 2002). Apelin was also highly expressed in adipocytes. As a hormone released by adipose tissue, apelin belongs to adipokines family. Adipokines display many properties, such as pro-inflammatory classical cytokines (tumor necrosis factor alpha [TNF-α], interleukin-6 [IL-6]), chemokines (monocyte chemoattractant protein-1), proteins involved in vascular homeostasis (plasminogen activator inhibitor), regulation of blood pressure (angiotensinogen), glucose homeostasis (adiponectin), lipid metabolism (retinol binding protein), and angiogenesis [vascular endothelial growth factor [VEGF](Trayhurn et al., 2006)].

Its extensive tissue distribution suggests, that the apelin/APJ system, also known as an apelinergic system, might be involved in many physiological processes, such as regulation of body fluid homeostasis (Reaux et al., 2001), blood pressure (Tatemoto et al., 2001), endocrine stress response (Taheri et al., 2002; O'Carroll et al., 2003), cardiac contractility (Szokodi et al., 2002), angiogenesis (Zhang et al., 2016), and energy metabolism (Bertrand et al., 2015). Additionally, apelin participates in pathological processes, including heart failure (Földes et al., 2003), obesity (Boucher et al., 2005), diabetes (Li et al., 2006), and cancer (Wang et al., 2008).

Under normal conditions apelin and APJ are expressed in cardiac myocytes. Apelin has a positive inotropic effect in vitro (Szokodi et al., 2002) and is involved in lowering arterial blood pressure (Tatemoto et al., 2001), inducing arterial vasodilation (Japp et al., 2008), and improvement of cardiac output (Japp et al., 2010). The first connection between apelin and pathology of the cardiac system was made in 2003. Földes et al. demonstrated higher expression levels of apelin mRNA in failing human hearts in compared to normal tissue, and suggested, that apelin might be involved in the pathophysiology of human heart failure (Földes et al., 2003). Apelin increases cardiac output and lowers blood pressure and peripheral vascular resistance in patients with heart failure (Japp et al., 2010). Moreover, [Pyr¹]apelin-13 injection into a rat model of myocardial infarction resulted in decreased infarct size, and increased heart rate and serum nitric oxide level in consecutive days, indicating that apelin has a sustained cardioprotective effect against myocardial infarction (Azizi et al., 2013). Another study revealed the connection between dramatic improvement of cardiac function and significant upregulation of stromal cell-derived factor 1/C-X-C chemokine receptor type 4 expression in postmyocardial infarction mice after administration of apelin-13 (Li et al., 2012). This peptide can also abolish reactive oxygen species (ROS) formation, reduce oxidative stress and prevent cardiac hypertrophy (Foussal et al., 2010). Interestingly, the loss of apelin in apelin-knockout mice increased myocardial infarction mortality, infarct size, and inflammation, with a reduction of the prosurvival pathway via phosphatidyl inositol 3-kinase/protein kinase B (PI3K/Akt) (Wang et al., 2013).

Hypertension is a cardiovascular condition, characterized by increased arterial blood pressure. Long-term high blood pressure could be a risk factor for many cardiovascular events, such as coronary artery disease, stroke, ischemic heart disease, myocardial infarction, and peripheral vascular disease (Alam et al., 2017). Apelin and APJ mRNA expression levels were reduced in rats with hypertension (Akcilar et al., 2013), which correlates with the significantly lower level of plasma apelin in the group of newly diagnosed hypertensive patients (Sonmez et al., 2010). APJ could be responsible for the action of apelin on regulating blood pressure. The protein expression level of this receptor was decreased in myocytes isolated from the left ventricular tissue of hypertensive rats with heart failure, compared to the control group. After the exogenous infusion of [Pyr1]-apelin-13, APJ levels were significantly increased. Reduced left ventricular systolic pressure was observed in hypertensive rats after apelin administration (Pang et al., 2014). Multiple findings suggest, that the hypotensive effect of apelin and APJ receptor might be mediated through nitric-oxide synthase (eNOS) (Ishida et al., 2004). Studies examining olmesartan, an angiotensin II receptor antagonist, as a treatment for hypertension in rats with heart failure, also found, that apelin can be involved in regulation of the Akt/eNOS pathway. (Fukushima et al., 2010). The APJ receptor can also act as a pressure sensor to respond to cardiac hypertrophy. In H9c2 rat myocardial cells, static pressure (180 mmHg) increased the expression of APJ protein, activated the PI3K/Akt pathway, induced cell autophagy, and stimulated myocardial hypertrophy (Xie et al., 2014).

Several studies have demonstrated that apelin can be treated as a biomarker of cardiovascular diseases. In patients with coronary artery disease, serum apelin-12 levels were reduced (Kadoglou et al., 2010). Decreased myocardial (Chandrasekaran et al., 2010) and serum (Ye et al., 2015) apelin-12 production was also characteristic for patients with systolic left ventricular dysfunction disease. The secretion pattern of apelin-12, measured as a concentration of this peptide in the coronary sinus, aorta, and renal vein, differed to that of brain natriuretic peptide, an internal control exclusively produced in heart (Chandrasekaran et al., 2010). These findings were also verified by Helske et al., who demonstrated altered transcardiac arteriovenous gradients of circulating in serum apelin-12 in response to left ventricular pressure overload (Helske et al., 2010). The level of apelin-36 was measured in patients and rats with left ventricular hypertrophy. In both groups, while the expression of myocardial apelin decreased, apelin plasma levels increased. The correlation between plasma apelin and left ventricular mass index in human and rats demonstrated, that this peptide might be used as a biomarker of left ventricular hypertrophy (Falcão-Pires et al., 2010). Meta-analysis of data indicated, that serum apelin (all forms) might be a prominent athero-protective marker against the development of coronary artery diseases (Chen et al., 2017b). The expression changes of apelin/APJ system in cardiovascular diseases are shown in Table 1.

All of these results, suggest that apelin could be responsible for increased cardiac output and cardioprotective effect against myocardial infarction and oxidative stress. Furthermore, the apelinergic system can play an important role in the regulation of blood pressure, acting as a pressure sensor to respond to cardiac hypertrophy. The hypotensive effect of apelin could be mediated through the Akt/eNOS pathway. The role of the apelin/APJ system in cardiac hypertrophy was well summarized by Lu et al. (2017). Additionally, in patients with different cardiovascular diseases, such as coronary artery disease, systolic left ventricular dysfunction disease, and left ventricular hypertrophy, apelin concentration is also altered, suggesting that apelin peptides could be successfully used as a biomarker of cardiovascular system pathologies.

Hypoxia is a condition of the body often caused by interrupted blood flow, inflammation, sepsis or hypertension, leading to the release of hypoxia-inducible factor (HIF-1). This short-lived macromolecule is a transcription factor that modifies and regulates cell metabolism to increase or decrease oxygen concentration. Sustained hypoxia causes organ and tissue damage (Pozo Devoto et al., 2013). This condition enhances the expression of HIF-1, leading to upregulation of apelin/APJ signaling and activation of PI3K/Akt and extracellular signal-regulated kinase pathways (ERK) (Zhang et al., 2015a,b). The expression changes of the apelin/APJ system in organs under hypoxia are shown in Table 1.

The main reasons for hypoxia are ischemia and reperfusion (I/R)—pathological conditions characterized by restriction of blood delivery to organs and tissues. I/R contribute to a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease, and sleep apnea (Eltzschig and Eckle, 2011). Renal I/R can occur as a consequence of systemic hypotension, cardiac arrest, renovascular surgery, and aortic clamping. Various pharmacological methods have been investigated for the treatment of renal I/R injury (He et al., 2015). Sagiroglu et al. examined the effect of apelin on renal functions following renal I/R. In that study, apelin-13 administrated pre-operatively to a I/R rat model resulted in protective, functional, and histopathological effects of renal I/R injury (Sagiroglu et al., 2012). The same conclusions have been drawn in another study, indicating that apelin-13 applied after rat kidney I/R injury increased antioxidant enzyme activity in a dose-dependent manner, prevented lipid oxidation, and improved renal functions (Bircan et al., 2016). Incubation of rat primary Müller cells with apelin-13 caused increased cell viability, migration, and expression of glial fibrillary acidic protein and VEGF. This, in turn, led to the significant protection of Müller cells against hypoxia conditions (Wang et al., 2012; Lu et al., 2013).

Apelin is also able to protect the heart against I/R injury both in vivo and in vitro. When administrated immediately after ischemia to isolated perfused rat hearts, apelin-13 protected the heart, limiting infarct size and improving postischemic mechanical recovery (Rastaldo et al., 2011). On the other hand, administration of apelin-12 to rats before ischemia or at the beginning of reperfusion reduced I/R injury. This cardioprotective effect compromises prevention and attenuation of oxidative stress by increasing the activity of antioxidant enzymes in postischemic hearts. This leads to inhibition of lipid peroxidation and reduced ROS formation (Pisarenko et al., 2011, 2014; Pisarenko O. et al., 2015). A structural analog of apelin-12-modified apelin-12 (MA)- injected into isolated perfused rat hearts, also reduced cardiomyocyte damage and improved cardiac dysfunction. This cardioprotective effect was mediated by protein kinase C (PKC), PI3K, and MAPK/ERK kinase 1/2 signaling (Pisarenko O. I. et al., 2015). Several signal transduction pathways -PI3K/Akt, ERK, mitogen-activated protein kinase (MAPK), and eNOS—have been proposed as the mechanism underlying the protective effect of the apelinergic system. Each of these signaling pathways is involved in protection against I/R injury, especially by the modulation of endoplasmic reticulum stress-induced apoptotic activation during the first 24 h of reperfusion (Tao et al., 2011).

The apelinergic system is involved in cerebral ischemia. Apelin-13 reduced brain infarct size in a dose-dependent manner in a transient model of focal stroke in rats. The central applications of this peptide showed a protective effect against cerebral damage and brain edema, thus preventing apoptosis (Khaksari et al., 2012). Additionally, apelin-13 had an anxiolytic effect on rats exposed to chronic normobaric hypoxia. These rats exhibited anxiety-like behavior, which might be associated with inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in microglial of the hippocampus (Fan et al., 2017). This peptide is also involved in protecting the blood-brain barrier from ischemic injury. Administration of apelin-13 in a mouse model with middle cerebral artery occlusion resulted in reduced infarct volume. The authors indicated that this is connected with aquaporin-4 upregulation, which could be a result of the activation of the ERK and PI3K/Akt pathways (Chu et al., 2017). In the same experimental model, apelin-36 injection reduced infarct volume and neuronal apoptosis (Gu et al., 2013). The same conclusions were reached by Yang et al., demonstrating the neuroprotective effect of apelin-13 against I/R through PI3K/Akt and ERK pathways using a cerebral I/R mouse model (Yang Y. et al., 2014). Apelin-13 can also inhibit apoptosis of neuronal cells in I/R cerebral mice through inhibition of immunoreactivity of pro-apoptotic factors and promotion of immunoreactivity of anti-apoptotic factors (Yan et al., 2015). AMP-activated protein kinase (AMPK) could be the mediator of the anti-apoptotic protection of apelin, since apelin-13 upregulated its level after cerebral I/R in mice (Yang et al., 2016b).

In pulmonary hypertension, the level of pulmonary tissue and plasma apelin (all forms) was unchanged by hypoxia. Moreover, in arteries of normoxic rats, apelin modulated vasoconstrictor tone, which was not observed in hypoxic animals. However, the level of apelin in the right ventricle was related to right ventricular pressure, suggesting that apelin could be used as a pulmonary hypertension marker (Andersen et al., 2009). Exacerbation of pulmonary hypertension induced by hypoxia was observed in mice, and this effect was mediated by downregulation of eNOS. Moreover, the critical mediators of apelin-APJ signaling in pulmonary artery endothelial cells were AMPK and Kruppel-like factor 2. Reduced apelin-12 levels were also observed in patients with pulmonary hypertension, suggesting its importance in this disease (Chandra et al., 2011). Interestingly, in vitro studies on pulmonary arterial smooth muscle cells (PASMCs) have indicated that hypoxia increases proliferation and migration of these cells. PASMCs proliferation was related to activation of autophagy in response to hypoxia. Apelin treatment under hypoxic conditions resulted in a decrease in PASMCs proliferation and migration through inhibition of autophagy, regulated by activation of the PI3K/Akt/mechanistic target of the rapamycin (mTOR) pathway (Zhang et al., 2014).

In conditions combining obesity and cardiac I/R injury, apelin-13 administration to mice decreased myocardial expression of pro-apoptotic B-cell lymphoma 2 (Bcl-2)-associated X protein and increased the expression of anti-apoptotic Bcl-2, leading to reduced myocardial apoptosis. Inhibition of apoptotic cell death was associated with a reduction of hypoxia-induced ROS production and attenuation of oxidative stress through the forkhead box protein O1 pathway (Boal et al., 2016).

Another metabolic disease, diabetes mellitus, exerts metabolic changes in erythrocytes, leading to oxidative stress. In diabetic rats, erythrocytes deformability was altered in myocardial I/R injury. However, apelin-13 administration before ischemia had a protective effect against these perturbations (Kartal et al., 2017). Hypoxia could also induce apelin secretion in human adipocytes. The level of secreted apelin-13 and apelin-36 was increased in adipocytes, and HIF-1 was the major factor involved in this process (Geiger et al., 2011). Moreover, apelin has an antioxidant effect in adipocytes. Apelin peptide treatment decreased ROS production and increased activity of antioxidant enzymes, such as Cu/Zn superoxide dismutase, catalase, and glutathione peroxidase. Apelin could also attenuate the ROS-stimulated release of pro-inflammatory adipocytokines and free fatty acids (Than et al., 2014). Furthermore, in adipocytes after hypoxic exposure, HIF-1 was responsible for upregulation of apelin level in response to insulin (Glassford et al., 2007). Adipocyte-released apelin upregulated by hypoxia could play a critical role in the development of the functional vascular network in adipose tissue (Kunduzova et al., 2008).

To summarize, apelin plays a protective role against ischemia through the PI3K/Akt, ERK, MAPK, AMPK, and eNOS pathways. Apelin is also responsible for decreased ROS formation and increased activity of antioxidant enzymes in adipocytes. Apelin secreted by adipocytes could play an important role in vascular network development in adipose tissue.

Angiogenesis is the physiological process of forming new blood vessels from existing vessels. This process is crucial for supplying tissues with oxygen and nutrients and for removing metabolites, such as carbon dioxide. Prolonged angiogenesis often indicates a pathological condition, such as arthritis, diabetic retinopathy or cancer progression (Al-Abd et al., 2017).

In ischemic disorders, HIFs transcription factors are upregulated, leading to the alternation of the expression of the angiogenesis-related factors gene expression. The proliferation of mesenchymal stem cells and upregulation of HIF-1 expression could be mediated through the apelin-APJ/autophagy pathway (Li et al., 2015). Administration of apelin also promoted mesenchymal stem cells survival and vascularization under hypoxic-ischemic conditions. This process might be connected with upregulation of VEGF (Hou et al., 2017).

Apelin signaling is also essential for angiogenesis promotion during portal hypertension (Tiani et al., 2009). Furthermore, administration of apelin-13 to rats with ischemic stroke led to increased forming of new blood vessels (Chen D. et al., 2015). Hypoxia conditions might also induce the expression of adipocyte-derived apelin, which could have important consequences for the relationship between adipose tissue and endothelial vascular cell function in the control of angiogenesis (Kunduzova et al., 2008). One of the suggested mechanisms underlying the role of apelin in angiogenesis is activation of AMPK and PI3K/Akt signaling. Moreover, eNOS, an important mediator in angiogenesis, is activated through direct phosphorylation by AMPK and Akt (Yang X. et al., 2014; Zhang et al., 2016).

The apelin/APJ system might be involved in pathological angiogenesis (Wu et al., 2017). In a mouse model of oxygen-induced retinopathy, the expression of apelin was dramatically increased during hypoxia and was significantly higher than the expression of VEGF. Moreover, APJ was highly expressed in proliferative capillary endothelial cells. Additionally, the suppression of apelin expression in apelin-knockout mice led to a limited proliferation of endothelial cells but induced retinal vessel maturation by promoting pericyte recruitment (Kasai et al., 2010, 2013).

All of these results indicate that apelin might mediate angiogenesis by upregulation of HIF-1, VEGF, and VEGFR (vascular endothelial growth factor receptor 2), as well as by activation of the AMPK/eNOS and PI3K/Akt/eNOS pathways. During pathological retinal angiogenesis, the expression of apelin and APJ is also increased.

Adipokines are biologically active molecules secreted by adipose tissue, the complex organ, in which adipocytes are the main cellular component (Tapan et al., 2010). In addition to adipocytes, this dynamic tissue is also composed of stromal-vascular fraction, compromising blood cells, pericytes, endothelial cells, and adipose precursors. Adipose tissue does not only perform a fat storage function; it is also synthesizing some biologically active compounds, which regulate metabolic homeostasis (Coelho et al., 2013). Apelin, as a member of the adipose tissue-derived peptides, might contribute to obesity-related disorders. However, its role remains unclear and experimental findings have been inconsistent. In the studies examining obese young patients, the apelin-12 plasma level was decreased, relative to healthy patients, which could be associated with severity of insulin resistance and adiposity (Tapan et al., 2010; Kotanidou et al., 2015). However, another study found that its plasma level was significantly increased in obese female children in comparison to non-obese children (Ba et al., 2014). Another study reported increased apelin-12 serum concentration in patients with obesity and obesity-related insulin resistance, which could be caused by impaired insulin sensitivity (Krist et al., 2013). These opposite findings might be explained by differential expression of apelin across tissues. In the obese and insulin-resistant high-fat diet female mice, the plasma apelin-12 concentration was not altered, but the level of apelin gene-expression was elevated in white-adipose tissue and reduced in brown-adipose tissue, liver, and kidneys, suggesting that the apelinergic system could be implicated in several dysfunctions in these tissues under obesity (Butruille et al., 2013). Additionally, in obese patients after hypocaloric diet-induced weight loss, the plasma apelin (all forms) level was significantly decreased. The diet-induced changes in plasma apelin levels directly correlated with the diet-induced decrease of metabolic variables, such as plasma insulin and TNF-α levels. However, expression of apelin and APJ was also decreased after low-calorie diet (Castan-Laurell et al., 2008).

Some data have indicated that there is a correlation between plasma insulin level and apelin expression in adipocytes. Administration of insulin into obese mice increased apelin gene transcription, what could be associated with activation of the PI3K/Akt, PKC, and MAPK pathways (Boucher et al., 2005). Apelin is also involved in a decrease of lipolysis in adipocytes. Administration of [Pyr1]-apelin-13 inhibited isoproterenol-induced lipolysis in cultured adipocytes through two possible mechanisms: attenuating PKA-mediated or increasing AMPK-mediated Ser-563 hormone-sensitive lipase phosphorylation (Yue et al., 2011). Another research revealed, that [Pyr1]-apelin-13 inhibited adipogenesis of pre-adipocytes by the AMPK and MAPK/ERK pathways. Moreover, exogenous apelin decreased the number of differentiated adipocytes and increased the size of lipid droplets inside the cells, suggesting that apelin might suppress lypolysis (Than et al., 2012).

Interestingly, adipose tissue growth is correlated with angiogenesis. The accumulation of adipocytes occurring under obesity could be closely linked with the structure and function of lymphatic vessels. Apelin signaling leads to enhanced lymphatic and blood vessels integrity. Increased permeability of lymphatic and blood vessels induced by dietary fatty acids, which leads to a block of fat accumulation was inhibited by apelin (Sawane et al., 2013).

These results hint that apelin might play an important role in obesity. The plasma apelin level is changed in obese patients compared to non-obese controls. Apelin inhibits lipolysis in adipocytes and is involved in angiogenesis in adipose tissue. However, the findings of studies investigating the role of apelin in obesity are inconsistent, and there are still many gaps in this topic. The expression changes of the apelin/APJ system under obesity are shown in Table 2.

Apelin is expressed in human, mouse, rat, pig and cat pancreatic islets and is regulated by glucocorticoids, but not by glucose (Ringström et al., 2010). Apelin plays a beneficial role in energy metabolism by increasing glucose uptake and insulin sensitivity (Bertrand et al., 2015). However, many controversies surround the relationship between apelin signaling, insulin sensitivity, and glucose uptake, which are discussed in the review by Xu et al. (2011). In diabetic patients apelin-12 concertation was increased (Habchi et al., 2014), extending susceptibility to diabetes (Zheng et al., 2016), thus, examining plasma apelin level could be used as a method to predict the development of type 2 diabetes (Ma et al., 2014; Hu et al., 2016). Furthermore, an augmented level of apelin in rats suggests, that it has a strong anti-type 2 diabetic activity and acts as an insulin-sensitizing agent (Akcilar et al., 2015).

Administration of apelin-13 to mice results in an eNOS-dependent decrease in glycemia and stimulation of glucose turnover. Moreover, AMPK signaling was a potential upstream target of eNOS-mediated stimulation of glucose transport (Dray et al., 2008). Additionally, [Pyr1]-apelin-13 increased glucose uptake in adipocytes by inducing translocation of glucose transporter type 4 (GLUT-4) in a PI3K/Akt-dependent manner and mediated inflammatory response in insulin-resistant adipocytes (Zhu et al., 2011). Apelin could also be involved in regulation of blood glucose level by AMPK activation and cAMP decrease (Alipour et al., 2017).

In diabetes-related diseases, such as diabetic retinopathy or nephropathy, the apelin-13 level was significantly elevated in comparison to non-diabetic organs. Furthermore, in the kidneys diabetic rats, administration of apelin-13 restored the downregulated expression of the antioxidant enzyme catalase, suggesting a renoprotective effect of apelin through antioxidant pathways (Day et al., 2013). Apelin was also responsible for podocyte apoptosis, which was negatively correlated with podocyte autophagy in diabetic mice with nephropathy. Moreover, the mTOR pathway has been proposed as the mechanism responsible for inhibition of podocyte autophagy by apelin. Additionally, apelin-13 might play a role in retinal neovascularization under diabetic retinopathy (Tao et al., 2010; Day et al., 2013; Liu et al., 2017). In mice with diabetic cardiomyopathy, adenoviral administration of the apelin gene led to increased expression of VEGF/VEGFR2 and angiopoietin-1/tyrosine-protein kinase receptor. Overexpression of apelin resulted in augmented myocardial angiogenesis, attenuated diabetic cardiac hypertrophy, and improved cardiac function (Zeng et al., 2014; Hou et al., 2015). There is also a connection between type 2 diabetes and cancer. A positive correlation was observed in vitro in breast, colon, and pancreas cancers. Hyperinsulinemia is likely the major factor, that plays a role in these associations. Insulin resistance, which leads to hyperinsulinemia, might serve as a potential target for cancer therapy (Cannata et al., 2010). The expression changes of the apelin/APJ system under diabetes mellitus and diabetes-related diseases are shown in Table 2.

All these findings indicate that the stimulation of glucose uptake by apelin is possible through translocation of GLUT-4 in a PI3K/Akt-dependent manner. In this process, the AMPK/eNOS pathways are also involved. In diabetes-related diseases, such as retinopathy, nephropathy or cardiomyopathy apelin has a protective effect against oxidative stress and apoptosis through the mTOR pathway.

Obesity is a condition that might increase the risk of cancer development. Storage of excess calories in the form of lipid results in extensive endocrine signaling from adipose tissue to the rest of the body. This connection is possible through adipokines secretion into the bloodstream, which connects with other metabolic organs. Therefore, it is likely that adipokines have a role in cancer development (Zhang et al., 2017). Numerous studies have demonstrated that increased BMI is associated with several types of cancer, such as prostate cancer, breast cancer, and esophageal adenocarcinoma (Paz-Filho et al., 2011). Interestingly, obesity regulates the expression of the genes connected with carcinogenesis. In the breast cancer cells of rats with diet-induced obesity, higher fold changes were detected in the expression of genes related to cellular proliferation, such as aldehyde dehydrogenase 3 family member A1 and MYC proto-oncogene. Also, the expression of the genes that protect from oncogenesis was modulated. The expression level of sirtuin-1, tensin homolog, and TGF-β were downregulated, whereas glutathione S-transferase Mu 2 and tumor protein p53 gene expression were upregulated in diet-induced obesity rats (Crujeiras et al., 2016). The level of the apelin peptide is elevated in several cancer types connected with adiposity. In obese men with colon cancer, the level of plasma apelin-12 is increased compared to a non-obese control (Al-harithy and Al-otaibi, 2015). In obese women with endometrial and breast cancer, the level of apelin-36 is also increased and positively correlated with BMI, fasting insulin levels, metabolic changes in fat tissues, hyper-inflammation, and neovascularization (Altinkaya et al., 2015; Cabia et al., 2016; Salman et al., 2016).

Expression of apelin/APJ occurs widely in many tissue types, indicating the involvement of the apelin/APJ system in numerous physiological processes, such as angiogenesis, energy metabolism, and the regulation of fluid homeostasis and cardiovascular system. However, alternation of the microenvironmental conditions leading to the pathological process might produce a shift in the role of apelin. Therefore, the apelinergic system can participate in some pathologies, including heart failure, hypoxia-related diseases, obesity, diabetes, and cancer. The importance and effect of the apelin/APJ system are altered under pathological conditions. In failing human heart, apelin has a cardioprotective effect against myocardial infarction. Elevated apelin expression increases cardiac output, lowers blood pressure, and attenuates oxidative stress and hypertrophy. Moreover, this peptide can be treated as a biomarker for cardiovascular diseases. During hypoxia, apelin acts as a protector against apoptosis and increases the activity of antioxidant enzymes reducing oxidative stress. This peptide is also involved in hypoxia- and cancer-related angiogenesis. Secreted by adipose tissue apelin might contribute to obesity-related disorders and diabetes mellitus. Altered serum apelin levels have been detected in multiple tissues under obesity and diabetes and could be a therapeutic target in the treatment of this pathologies. Furthermore, apelin serum level is positively correlated with BMI and could increase the risk of cancer development. The role of apelin in various processes is probably mediated through several signaling pathways. Processes leading to metastasis, migration and invasion are mediated through the PPAR, PI3K/Akt/mTOR, MAPK, and PAK1/cofilin pathways. The apelinergic system also has an influence on processes connected with energy metabolism, including glucose uptake, lipolysis and fatty acid oxidation, via the AMPK/eNOS and PI3K/Akt pathways. The AMPK/eNOS, PI3K/Akt, and MAPK pathways could mediate angiogenesis and I/R protection. An overview of the apelin-induced signaling pathways is shown in Figure 2. Regulation of progression of tumor growth and metastasis is the most recently discovered function of apelin. Many data indicate that in multiple cancer types, apelin and its receptor might be used as a prognostic biomarker. However, in many studies, the available results are unclear. First, the expression changes of apelin/APJ mRNA do not correlate with its serum concentrations. Moreover, not all forms of apelin peptides are examined, or there is no distinction between peptide types. Additionally, the antibodies used in experiments are often non-specific and recognize more than one form of apelin. Interestingly, apelin receptor antagonists could be promising therapeutic compounds for cancer treatment. Nevertheless, the most often used antagonist—ML221—could also inhibit more receptor types (e.g., kappa opioid or the benzodiazepinone receptors) (Maloney et al., 2012). This result suggests that ML221 could inhibit another receptor and act through different signaling pathways. After appraising the available data, we propose that there remains much to learn about the role of apelin in pathological processes.

MW, KP-G, and DN contributed conception and design of work. MW wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.