Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2018 Dec 26;234(8):12149–12160. doi: 10.1002/jcp.27942

Apelin/APJ system: A potential therapeutic target for endothelial dysfunction‐related diseases

Jun Cheng 1,†, Xuling Luo 1,†, Zhen Huang 1,2,✉, Linxi Chen 1,✉
PMCID: PMC13484158  PMID: 30585633

Abstract

APJ is a G protein‐coupled receptor and its endogenous ligand is apelin. Studies have shown that apelin/APJ system is widely distributed in the body, especially highly expressed in the vascular endothelial cells (ECs). Numerous reports have demonstrated that apelin/APJ system plays an important role in the regulation of ECs function. Our lab has demonstrated that apelin‐13 is able to promote adhesion of monocyte‐human umbilical vein EC via 14‐3‐3, and reactive oxygen species‐autophagy signaling pathways. In this review, we concentrate on the regulatory mechanism of apelin/APJ system in EC, including promotion of proliferation, migration, and angiogenesis. Moreover, we also analyze the role of apelin/APJ on endothelial dysfunction‐related diseases including atherosclerosis, diabetes, hypertension, and myocardial infarction. Finally, we summarize the most commonly used agonists and antagonists of APJ. Therefore, apelin/APJ system is expected to be a therapeutic target for the treatment of endothelial dysfunction‐related diseases.

Keywords: agonists, antagonists, apelin, endothelial cells

This review summarizes the link between the apelin/APJ system and EC dysfunction‐related diseases, providing ideas for future treatment of the disease.

graphic file with name JCP-234-12149-g002.jpg

1. INTRODUCTION

APJ, first discovered as a new member of G protein‐coupled receptors (GPCR) in 1993, shares 40–50% of the hydrophobic transmembrane regions with the angiotensin receptor (AT1; O’Dowd et al., 1993). Until 1998, Tatemoto et al. isolated APJ receptor ligand from bovine stomach extracts, which named apelin (Tatemoto et al., 1998). The preproprotein of apelin contains 77 amino acids, which can be enzymatically hydrolyzed into more active biological fragments, like apelin‐36, ‐17, ‐16, ‐13, ‐12, and pyroglutamate modified form of apelin‐13 ([Pyr1]‐apelin‐13; Chaves‐Almagro et al., 2015). Recently, a new endogenous ligand of the APJ receptor (Elabela) was also found (Chng, Ho, Tian, & Reversade, 2013). Among these isoforms, apelin‐13 has the most biologically active and most commonly use.

Apelin/APJ system is abundantly distributed in various tissues and cells of the human body. To date, studies have demonstrated that apelin can be detected in the right atrium, left ventricle, brain, lung, liver, and adrenal, especially highly expressed on endothelial cells (ECs) and smooth muscle cells (Kleinz & Davenport, 2004; Zhao, Yao, Li, & Chen, 2007). As we know, ECs are important components of blood vessels. Research have shown that apelin/APJ could act on ECs to regulate vascular function, including lowering blood pressure (Yeganeh‐Hajahmadi, Najafipour, & Rostamzadeh, 2017), promoting adhesion of monocytes to human umbilical vein ECs (X. Li et al., 2010; M. Liu et al., 2018), enhancing angiogenesis and vasodilation (Y. Li et al., 2018). Therefore, apelin/APJ plays an important role in the regulation of EC function.

Recently, a growing body of research has been focused on the role of the apelin/APJ system in vascular ECs. Eyries et al. (2008) demonstrated that hypoxia promoted apelin expression, which enhanced ECs proliferation and regenerative angiogenesis. Zhang et al. (2016) verified that increase expression of apelin enhanced hypoxia‐induced marrow‐derived endothelial progenitor cells (EPCs) growth. Moreover, apelin/APJ axis also regulates the cardiovascular system, fluid homeostasis, metabolic pathways, and angiogenesis through different signaling pathways and ECs polarization (Kasai et al., 2010; Kwon et al., 2016; Lv, Yang, & Chen, 2013). Thus, apelin/APJ system can participate in the regulation of vascular homeostasis by acting on ECs. In this review, we elaborate on the mechanism of apelin/APJ system on ECs, such as proliferation, migration, as well as angiogenesis. Additionally, we discuss the role of apelin/APJ system in endothelial dysfunction‐related diseases, including atherosclerosis (AS), diabetes mellitus, hypertension, and myocardial infarction.

2. THE ROLE OF APELIN/APJ SYSTEM IN THE PHYSIOLOGY OF ECS

2.1. Apelin/APJ system promotes ECs proliferation

In normal blood vessels, mature ECs proliferate very low, however, under some stimuli, ECs re‐enter the cell cycle for proliferation. Several studies have confirmed that a number of molecules can promote the proliferation of ECs, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and apelin (S. Guo et al., 2012; J. Hou et al., 2017; Shen, Shoichet, & Radisic, 2008). It has been reported that apelin is a mitogen for ECs. Stimulated by some factors, like loss of shear forces, all‐trans retinoic acid (ATRA), VEGF, or hypoxia, apelin expression can be upregulated, which promoted the proliferation of ECs (Kidoya et al., 2008; Sheikh et al., 2008; Shi, Yuan, Yang, & Zang, 2017). In 2004, apelin was found to promote the proliferation of human umbilical endothelial cells (HUVEC) by activating the ERK/PI3K‐p70S6K pathways (Masri, Morin, Cornu, Knibiehler, & Audigier, 2004). In the same year, Kasai et al. (2004) also observed that apelin significantly enhanced the proliferation of retinal EC line RF/6A. Later, X. Yang et al. (2014) found that apelin‐13 promoted the proliferation of myocardial microvascular endothelial cells (MMVECs) via phosphorylation of AMP‐activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Moreover, Zhang et al. (2016, 2015) have demonstrated that hypoxia upregulated the apelin/APJ signaling system, which promoted the proliferation of EPCs through PI3K/Akt and MAPK signaling pathways.

Besides, there are also lie in some protein molecules that inhibit apelin activity. Bone morphogenetic protein (BMP) was shown to abolish the proliferation of ECs by activation of the BMPR2 and smad pathways (Poirier et al., 2012). Recently, Kim et al (2013) and Wen et al. (2018) reported that microRNA‐503 (miR‐503) inhibited the proliferation of pulmonary artery endothelial cells (PAECs) and EPCs through targeting apelin. Therefore, these findings indicate apelin/APJ is an important regulator of ECs proliferation. But further studies are required on how apelin affects ECs proliferation (Figure 1).

Figure 1.

Figure 1

Open in a new tab

Apelin/APJ system promotes the proliferation of EC. AKT: protein kinase B; AMPK: AMP‐activated protein kinase; EC: endothelial cells; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal–regulated kinases; MAPK: mitogen‐activated protein kinases; PI3K: phosphoinositide 3‐kinase [Color figure can be viewed at wileyonlinelibrary.com]

2.2. Apelin/APJ system promotes ECs migration

The migration of ECs occurs not only in the process of embryonic vascularization, but also in various pathological or physiological processes in the adult vasculature, such as vessel repair, tissue damage, angiogenesis (Plein, Fantin, Denti, Pollard, & Ruhrberg, 2018). Accumulating studies proved that apelin can promote ECs migration (Kleinz & Davenport, 2004; Kunduzova et al., 2008). Using long‐term time‐lapse video microscopy in two‐dimensional cell cultures, Berta et al. (2014) discovered that apelin increased lymphatic endothelial cells (LECs) migration. Kwon et al. (2016) found that apelin promoted the migration of ECs by affecting its polarization which induced by blood‐flow shear stress. In contrast, other studies have shown that knockdown of APJ inhibited apelin‐induced ECs migration, whereas knockdown of apelin had no effect on that (Busch et al., 2015; Kunduzova et al., 2008; Strohbach et al., 2018).

In addition, ECs migration is able to affect the caliber size of blood vessels (Takakura & Kidoya, 2009). Vascular caliber size is mainly regulated by the Ang1/Tie2 and VEGF/VEGFR systems. Noteworthy, Tie2 is a receptor tyrosine kinase of Ang1, which is widely distributed in the vascular endothelium. When Tie2 (a receptor of tyrosine kinase) is activated on ECs, which will induce the production of apelin, and apelin will regulate the diameter of blood vessels (Kidoya et al., 2008). Recently, Christian et al. confirmed that hemangioblast, which is an EC precursor, can rely on the expression of apelin receptors for migration to the midline of the vasculature (Helker et al., 2015). Thus, all of these results indicate that apelin/APJ is capable to promote ECs migration.

2.3. Apelin/APJ system promotes ECs angiogenesis

Angiogenesis refers to the process of forming new blood vessels from pre‐existing capillaries, often occurs in the embryogenesis and postnatal of life, and plays a pivotal function in physiological and pathological conditions, such as tumor growth, myocardial infarction, and wound healing (Kalin et al., 2007; Ko & Bandyk, 2014; B. R. Yang et al., 2016). Angiogenesis is an extremely complicated process, involving in several interrelated steps: including ECs migration, proliferation, and capillary tube formation. We have previously described in detail the mechanism by which apelin participates in the first two aspects of angiogenesis. In fact, there are reports on the involvement of apelin taking part in the formation of cell tubes (Novakova, Sandhu, Dragomir‐Daescu, & Klabusay, 2016; Patel et al., 2014). Hence, apelin/APJ system is closely related to the process of angiogenesis.

Since Kasai et al. (2004) first reported that apelin was an angiogenic factor in retinal ECs. In 2006, Cox et al. also proved that apelin had angiogenic activity and the formation of clear capillary‐like in both in vivo Matrigel plug assays and experiments with frog embryos and chick chorioallantoic membrane assay (Cox, D’Agostino, Miller, Heimark, & Krieg, 2006; Kunduzova et al., 2008). Moreover, apelin was shown to induce the sprouting and the proliferation of ECs from the retinal vascular network by injecting in the vitreous (Masri, van den Berghe, Sorli, Knibiehler, & Audigier, 2009). In addition, in human non‐small‐cell lung cancer (NSCLC), exogenous apelin increased tumor growth and microvessel densities and perimeters in vivo (Berta et al., 2010). On the contrary, knockdown of apelin or the use of apelin and APJ inhibitors can inhibit angiogenesis. In apelin‐deficient (apelin‐KO) mice, Kasai et al. (2008) demonstrated that the retinal vascularization and eye development suppressed. Tiani et al. (2009) showed that the formation of visceral neovascularization reduced when treatment with the APJ antagonist F13A in the model of portal hypertension rats. The study by del Toro et al. (2010) indicated that knockdown of apelin in mice and zebrafish, angiogenesis was delayed. In addition, Ishimaru, Shibagaki, Yamamuro, Yoshioka, and Maeda (2017) demonstrated that another antagonist of APJ, ML221, inhibited pathological retinal angiogenesis in a mouse model of oxygen‐induced retinopathy (OIR). In conclusion, apelin/APJ system can promote angiogenesis.

Simultaneously, scientists conducted an in‐depth study on the specific mechanism of apelin/APJ system to promote angiogenesis. Visser, Walther, Laghmani el, Laarse, and Wagenaar (2010) demonstrated that apelin treatment improved pulmonary angiogenesis through the NO‐cGMP signaling pathway in a mouse model of neonatal hypoxia‐induced lung injury. Report from L. Li, Zeng, and Chen (2012) showed that apelin promoted the homing of vascular progenitor cells and the regeneration of capillaries in ischemic areas after myocardial infarction by upregulating the SDF‐1α/CXCR‐4 signal axis. Yang et al. (2014) found that apelin‐13 promoted angiogenesis via the activation of AMPK and Akt signaling in MMVECs. In the rat post‐MI model, scientists have discovered that the apelin/APJ system has different regulatory pathways for angiogenesis. Azizi et al. (2015) showed that [Pyr1]apelin‐13 increased the expression of angiogenic molecules, like VEGF, Ang‐1, and eNOS. Heng et al. demonstrated that apelin‐attenuated angiogenesis by inhibiting the activation of Sirt3 (X. Hou, Zeng, He, & Chen, 2015). In addition to these, D. Chen, Lee, Gu, Wei, and Yu (2015) implicated that apelin‐13 increased the expression of VEGF and matrix metalloproteinase‐9 (MMP9), which promoted angiogenesis in a mouse model of focal ischemic stroke. Recently, there are some reports confirmed that Elabela is also participating in the regulation of angiogenesis in adult and embryonic stages (Helker et al., 2015; Wang et al., 2015). Besides, Pi et al. (2017) created Apln‐CreERT: mT/mG reporter mouse line, which could be a useful tool for studying local tissue angiogenesis. Above all, apelin/APJ system is not only to be a marker for angiogenesis but also a potential target for the treatment of angiogenesis‐related diseases (Figure 2).

Figure 2.

Figure 2

Open in a new tab

Apelin/APJ system promotes the angiogenesis of endothelial cells. AKT: protein kinase B; AMPK: AMP‐activated protein kinase; cGMP: cyclic guanosine monophosphate; eNOS: endothelial nitric oxide synthase; ERK: extracellular signal–regulated kinases; MMP9: matrix metalloproteinase; NO: nitric oxide; SDF‐1: stromal‐derived factor‐1; VEGF: vascular endothelial growth factor [Color figure can be viewed at wileyonlinelibrary.com]

3. REGULATION OF THE APELIN/APJ SYSTEM IN ENDOTHELIAL DYSFUNCTION‐RELATED DISEASES

3.1. Atherosclerosis

AS is a chronic inflammatory disease. When endometrial integrity is damaged, low‐density lipoprotein (LDL) will enter into the subepithelial space, oxidatively modified LDL is recognized and ingested by macrophages, and thus form the foam cells. Besides, the process coupled with infiltration of inflammatory factors, proliferation, and migration of vascular smooth muscle cells. All these finally leading to the formation of AS (Bonetti, Lerman, & Ler man, 2003).

A large number of studies have shown that there is a close relationship between apelin/APJ system and atherosclerosis. It is reported that a low level of apelin expression in patients with high LDL (Tasci et al., 2007). In the apoE‐deficient atherosclerosis mice model, Chun et al. (2008) discovered that apelin signaling blocked Ang II‐induced atherosclerosis, the reason might be that apelin was capable to activate NO synthase (eNOS) phosphorylation pathways. In addition, Kourtis et al. (2011) demonstrated that apelin was negatively associate with HDL‐cholesterol and ox‐LDL in the pregnancy group. Kostopoulos, Spiroglou, Varakis, Apostolakis, and Papadaki (2014) showed that apelin and APJ immunostaining was detected in atherosclerotic lesions. they inferred that apelin/APJ expression likely to be inversely associated with human aortic and coronary atherosclerosis. However, Rittig et al. (2011) found that serum apelin level can not be considered as an early risk indicator in young subjects prone to atherosclerosis. A study from Kadoglou et al. (2012) reported that low apelin serum levels were correlated with carotid plaque vulnerability, and it seems that the atorvastatin‐induced modification of apelin beneficially interplay with the carotid plaque stabilization. Similarly, Zhou, Wang, and Qiao (2014) indicated that the levels of plasma apelin were inversely correlated with the severity of coronary artery stenosis, whereas it positively related with the stability of atherosclerotic plaque in humans with acute coronary syndrome. The reason that apelin produces different results for atherosclerosis may be due to factors such as different periods of atherosclerosis, the type and location of the specimen, and the detection method.

In fact, studies have shown that apelin, as an important cardiovascular active peptide, can regulate every pathological process of atherosclerosis. Our laboratory previously summarized apelin/APJ system was involved in the development of atherosclerosis by affecting vascular smooth muscle cells (Luo, Liu, Zhou, & Chen, 2018). Besides, apelin also affects the development of atherosclerosis through lipid metabolism. In APJ and apolipoprotein E double‐knockout (APJ(−/−)ApoE(−/−)) mice fed a high‐cholesterol diet, atherosclerotic lesions were significantly reduced than that of control group (Hashimoto et al., 2007). Similarly, in ApoE(−/−)TIMP3(−/−) mice fed a chow diet, accumulation of neutral lipids was found in the heart. They confirmed that it is the metabolic defect caused by the lack of apelin (Stohr et al., 2015). In addition, X. Y. Liu et al. (2013) found that apelin‐13 seems to activate PKCα, phosphorylate ABCA1 and inhibit calpain‐mediated proteolysis, hence promoting cholesterol efflux and reducing foam cell formation. Moreover, it is shown that apelin‐13 was capable of reducing lipid accumulation of foam cells by activating autophagy through Class III PI3K/Beclin‐1 pathways (Yao et al., 2015). Apelin‐13 also showed to downregulate the expression of LPL by activating the APJ/PKCα/miR‐361‐5p signaling pathway in THP‐1 macrophage‐derived foam cells, which leads to inhibition of lipid accumulation and proinflammatory cytokine secretion (Zhang et al., 2016).

Besides, apelin is involved in the adhesion of monocytes(MCs) to ECs in the process of atherosclerosis. Our previous works have demonstrated that apelin‐13 promoted the adhesion of MCs to HUVECs via the 14‐3‐3, reactive oxygen species‐autophagy signaling pathways (X. Li et al., 2010; S. Liu et al., 2018). Furthermore, Y. Lu et al. (2012) found that apelin‐13 increased inflammation molecules and chemokines (intercellular adhesion molecule‐1 [ICAM‐1], vascular cell adhesion molecule 1 [VCAM‐1], and monocyte chemoattractant protein‐1 [MCP‐1]) via NF‐κB/JNK signal pathways in HUVECs.

Therefore, although most experimental evidence suggests that apelin has an inhibitory effect on atherosclerosis, this conclusion is controversial and more experiments are needed to further support this view.

3.2. Diabetes mellitus

Diabetes mellitus (DM), characterized by hyperglycemia continue for a period of time, is a group of metabolic disorders. Long‐term hyperglycemia reduces insulin sensitivity and causes dysfunction of cells or tissues, which ultimately manifested in vasoconstriction, angiogenesis, as well as disorders of glucose and lipid metabolism (Boucher et al., 2005; Castan‐Laurell et al., 2008; Kolluru, Bir, & Kevil, 2012). Increasing evidence suggests that apelin is closely associated with diabetes and its complications. Ringström et al. found that apelin was mainly expressed in both β cells and α cells in the islet, whereas APJ‐receptor was detected in islets cells, pancreatic duct as well as acinar cells (Kapica et al., 2012; Ringström et al., 2010).

To date, researchers are controversial about the level of apelin in insulin. Soriguer et al. (2009) demonstrated that the levels of apelin were increased in the morbidly obese and type 2 diabetic patients. The findings by Dray et al. (2010) in diabetic patients also support this relationship. Whereas other studies have shown that plasma apelin levels are reduced in patients with type 2 diabetes and type 2 diabetic rats (Erdem, Dogru, Tasci, Sonmez, & Tapan, 2008; Kadoglou et al., 2010; Kursunluoglu‐Akcilar, Kilic‐Toprak, Kilic‐Erkek, Turgut & Bor‐Kucukatay, 2014). Although the reason for this difference results may be multifactorial, more evidence suggests that apelin has the effect of lowering blood glucose, improving insulin sensitivity. In food‐fed mice, Dray et al. found that acute intravenous apelin reduces the effects of glucose in the blood, which is associated with increased glucose utilization in skeletal muscle and adipose tissue. In addition, they also verified that EC NO synthase, AMP‐activated protein kinase, and Akt are involved in apelin‐stimulated glucose uptake in soleus muscle (Dray et al., 2008). In an apelin deficient mice model, Yue et al. found the phenomenon of insulin sensitivity and hyperinsulinemia, which may be caused by AMPK‐dependent signaling pathway (Yue et al., 2010). Moreover, in 3T3‐L1 adipocytes, apelin stimulates glucose uptake through the PI3K/Akt pathways (Zhu et al., 2011). Thus, apelin can be used as an important factor in the regulation of blood glucose and participate in the regulation of diabetes.

In addition, a large number of reports that apelin is also involved in the regulation of diabetic complications. Diabetic nephropathy is one of the common complications of diabetes. Some causes such as inflammation, increased glomerular permeability, injured podocyte dysfunction, and impaired myogenic responses, all of which contribute to the progression of diabetic nephropathy. Zhang, Wang, Wang, Yin and Zeng (2013) found that apelin increases permeability via upregulating the expression of VEGFR2 and Tie2 in glomerular ECs. Furthermore, in a model of diabetic mice, increased apelin concentration neutralizes APJ‐mediated myogenic reactions and promotes the progression of diabetic nephropathy (Zhang, Yin, Wang, Li & Zheng, 2018). Recent studies have found that apelin also promotes the reduction of podocyte proteasome activity by inducing endoplasmic reticulum stress, and induces podocyte dysfunction by ERK‐, Akt‐ and mTOR‐dependent pathways, which are involved in the development of diabetic nephropathy (C. Guo et al., 2015; Y. Liu, Zhang, Wang, & Zeng, 2017). Whereas, another study indicated that apelin‐13 can be used as a candidate for the treatment of diabetic nephropathy by promoting histone acetylation (H. Chen et al., 2014). In summary, the difference in the effect of this apelin on diabetic nephropathy may be due to the different types of mice.

In contrast, apelin is confirmed to be a potent angiogenic factor in retinal ECs, which promotes the development of diabetic retinopathy (Kasai et al., 2004, 2008). Tao et al. (2010) showed that the serum level of apelin‐13 has a positive connection with proliferative diabetic retinopathy, which independent of VEGF. Latter, Du et al. (2014) have similar findings. In human retinal pigment epithelial (RPE) cells, Qin, Zheng, and Jiang (2013) demonstrated that exogenous apelin enhances proliferation, migration, and collagen I expression via the PI3K/Akt and MEK/ERK signaling pathways. Additionally, pericytes are cells involved in normal vascular structures. It is reported that pericytes increase to form new blood vessels and inhibit pathological angiogenesis (Welen, Jennbacken, Tesan, & Damber, 2009). In the retinas of mice with OIR, Kasai et al. (2013) found that knockdown of apelin promotes recruitment of pericytes via upregulates MCP‐1 expression, which induces by smad3 activation. Furthermore, L. Chen, Tao, Feng, and Jiang (2015) showed that apelin inhibits hypoxia‐induced pericytes apoptosis by downregulating the expression of caspase‐3 (L. Chen, Tao, Feng, & Jiang, 2015).

Besides, apelin/APJ system and other complications of diabetes, such as diabetic cardiomyopathy, osteoporosis, diabetic neuropathy, and so forth have also been reported (Bilir et al., 2016; S. Liu et al., 2018; Zeng, He, Hou, Li, & Chen, 2014). Altogether, these findings correlated with previous studies which suggested that apelin might influence on the development of diabetes and could be used as a potential therapeutic target (Table 1).

Table 1.

Apelin/APJ is involved in endothelial dysfunction‐related diseases

Disease types Experiment models Treatment Pathways Effects References
Atherosclerosis APJ−/−ApoE−/− mice HCD NADH/NADH oxidase Inhibit Hashimoto et al. (2007)
ApoE−/− mice Apelin NO production Inhibit Chun et al. (2008)
Cell Apelin‐13 14–3‐3 Promote X. Li et al. (2010)
HUVECs Apelin‐13 NF‐κB/JNK Promote Y. Lu et al. (2012)
ApoE−/− TIMP3−/− mice HCD TIMP3‐apelin Promote Stohr et al. (2015)
THP‐1 cell Apelin‐13 PKCα Inhibit X. Y. Liu et al. (2013), Yao et al. (2015), and Zhang et al. (2017)
PI3K III/Beclin‐1;
APJ/PKCα/miR‐361–5p
Cell Apelin‐13 ROS‐autophagy Promote S. Liu et al. (2018)
Diabetes mellitus Diabetic db/db mice Apelin PI3K/Akt–eNOS Inhibit Ishida et al. (2004); Zhong et al. 2014)
Insulin‐resistant mice Apelin NO synthase; Inhibit Dray et al. (2010)
AMP‐activated protein kinase; Akt
Diabetic db/db mice Apelin AMPK Inhibit Yue et al. (2010)
3T3‐L1 adipocytes Apelin PI3K/Akt Inhibit Zhu et al. (2011)
Retinal pigment epithelial cells Apelin PI3K/Akt; MEK/Erk Promote Qin et al. (2013)
Rat retinal pericytes Apelin Caspase‐3 Inhibit Chen et al. (2015)
Diabetic KK‐Ay mice Apelin VEGFR2; Tie2 Promote Zhang et al. (2013), C. Guo et al. (2015), and Y. Liu et al. (2017)
ER; ERK; Akt; mTOR
Wistar rats Apelin l‐Arg/NOS/NO Inhibit Jia et al. (2007)
MCT rat Apelin miR‐424/503–FGF; Inhibit Bertero et al. (2014)
STAT3‐miR‐204
MCT rat Apelin CD39 Inhibit Helenius et al. (2015)
Sprague–Dawley rat Apelin analogs βarr recruitment Inhibit Besserer‐Offroy et al. (2018)
Myocardial infarction Cell Apelin PI3K/Akt; Inhibit Zeng et al. (2009)
ERK1/2
Langendorff‐perfused rat Apelin‐13 NO? Inhibit Rastaldo et al. (2011)
Post‐MI mice Apelin SDF‐1α/CXCR‐4; Sirt3 Inhibit L. Li et al. (2012) and L. Li et al. (2013)
MI mice [Pyr1]apelin‐13 NO; VEGFA; Kdr; Ang‐1; Tie2; eNOS Inhibit Azizi et al. (2013) and Azizi et al. (2015)
Sprague–Dawley rats Apelin‐13 NF‐κB Inhibit Zhang et al. (2015)
MI mice Elabela ERK1/2 Inhibit Perjes et al. (2016)
Apelin‐KO mice Apelin S1P Inhibit Tatin et al. (2017)
MI mice Apelin p‐Drp1ser 616 Inhibit Xu et al. (2017)
Open in a new tab

Note. Apelin‐KO mice: apelin‐deficient mice; CD39: cluster of differentiation; HCD: high‐cholesterol diet; HUVECs: human umbilical vein endothelial cells; MCT rat: monocrotaline‐treated rat; NO: nitric oxide; NF‐κB: nuclear factor‐κB; Post‐MI: post myocardial infarction; ROS: reactive oxygen species; VEGFR2: vascular endothelial growth factor receptor 2.

3.3. Hypertension

Hypertension is the main feature of increasing the pulse pressure of the body cycle. It caused by multiple genetic inheritances, environment, and multiple risk factors, and often accompanied by functional and organic damage of organs such as the heart, brain, and kidney. Recent studies have shown that apelin/APJ system has a certain relationship with hypertension. Lee et al. (2000) injected exogenous apelin into rats and found that both systolic and diastolic blood pressures decreased immediately. Soon after, a report from Tatemoto et al. (2001) showed that apelin subtype, apelin‐12, − 13, − 36, can reduce the mean arterial pressure in rats, and the mechanism may be related to the production of nitric oxide. Additionally, in rat‐induced hypertensive models (e.g., deoxycorticosterone acetate‐salt‐induced hypertensive model and two‐kidney‐one‐clip hypertension model), both the reduction of serum apelin and the downregulation of APJ were found (Akcılar et al., 2013; Najafipour et al., 2015). Data from clinical also indicate that patients with hypertension appear to have lower levels of apelin in the serum than health controls. Papadopoulos et al. (2013) demonstrated that masked hypertension have lower apelin compared with normotensive controls. Similar to that observed in other types of hypertensive patients (e.g., patients with left ventricular hypertrophy and hemodialysis patients with pulmonary arterial hypertension; Samareh Fekri, Etminan, Rashidnedjad, Mojibian & Masoomi, 2018; Ye et al., 2015). Interestingly, some researchers have reached the opposite conclusion. A study showed that the expression of apelin in the rostral ventrolateral medulla (RVLM) of spontaneously hypertensive rats is enhanced, and overexpression of this gene in RVLM leads to an increase in chronic blood pressure in normal blood pressure rats (Zhang, Yao, Raizada, O'Rourke & Sun, 2009). Moreover, in a model of spontaneously hypertensive rats, Zhang et al. (2014) indicated that apelin‐13 and APJ in the paraventricular nucleus contribute to hypertension through sympathetic activation and vasopressin release. This seemingly contradictory results may be related to the location of apelin and the manner in which it is administered.

In addition, genetic is recognized as one of the important factors leading to hypertension. A study proved that essential hypertension may be associated with genetic variation in apelin (W. W. Li et al., 2009). Furthermore, Jin et al. (2012) confirmed by sequencing that the defects of apelin inheritance may bring risks to Chinese hypertensive patients. Recent findings also suggest that APLNR rs11544374 gene polymorphism may be a predisposing factor in hypertension (Nowzari et al., 2018).

So far, the mechanism of apelin/APJ system to regulate hypertension is multifactorial. Jia et al. (2007) confirmed that apelin induce rat aortic vasodilation by directly activating l‐Arg/NOS/NO pathways. In addition, miRNAs are highly expressed in the vasculature, and studies have shown that apelin can participate in the regulation of hypertension by regulating miRNAs (Kim et al., 2013). Bertero et al. (2014) reveal more sophisticated network regulation of miRNAs, which miR‐130/301 modulated apelin‐miR‐424/503‐FGF2 signaling in ECs, whereas miR‐130/301 modulated STAT3‐miR‐204 signaling in smooth muscle cells. Moreover, Helenius et al. (2015) demonstrated that apelin enhanced the activity of cluster of differentiation 39, which is an enzyme capable of hydrolyzing ATP and ADP into AMP on the surface of ECs, thereby exerting the effect of inhibiting hypertension. Recently, β‐arrestin recruitment was also found to involve in the activation of APJ, which lowers blood pressure (Besserer‐Offroy et al., 2018). According to these results, apelin has anti‐hypertensive potential and can be used as a new therapeutic target for the treatment of hypertension.

3.4. Myocardial infarction

The characteristic of myocardial infarction (MI) is left ventricular (LV) enlargement and reduced capillary density (Fukuda et al., 2004). As the first report that apelin has a positive inotropic effect in both normal rat hearts and rat hearts in failure after myocardial infarction, the relationship between apelin and myocardial infarction has received increasing attention (Chun et al., 2008). Noteworthy, there are some contradictory reports about apelin/APJ on myocardial infarction. In a rat model, Ronkainen et al. (2007) demonstrated that the levels of ventricular apelin messenger RNA (mRNA) would transient increase in acute myocardial infarction (24 hr). Another research group showed that the level concentrations of plasma apelin are higher in patients with ST‐elevation myocardial infarction (STEMI) than that of the controls (Sans‐Rosello et al., 2017). However, reports from other researchers showed that plasma apelin concentration is lower in patients with acute myocardial infarction compared with the control group (Weir et al., 2009). These conflicting results might be caused by the time of detection was different, and apelin was upregulated during ischemia but downregulated during reperfusion.

Even so, the data of apelin on animal models and human patients is encouraging. Exogenous administration of apelin‐13, ‐12, and structural analog of apelin‐12 can reduce infarct size and improve myocardial function recovery after ischemia (Pisarenko et al., 2011, 2012; Rastaldo et al., 2011). Conversely, apelin deficiency leads to an increase in infarct size and eventually to heart failure (Wang et al., 2013). Therefore, the mechanism of apelin on myocardial infarction is worthy of further study. In the in vivo and in vitro model of myocardial infarction, some groups have confirmed that both apelin and Elabela reduced infarct size by phosphorylating PI3K/Akt and ERK1/2 signal pathways (Perjés et al., 2016; Zeng et al., 2009). Furthermore, Azizi et al. and other scientists have shown that NO may limit the infarct size as a protective medium, and its expression can be increased by apelin‐induced (Azizi, Faghihi, Imani, Roghani, & Nazari, 2013; Rastaldo et al., 2011). Later, their further research showed that treatment with [Pyr1]apelin‐13 increased the expression of VEGFA, Kdr, Ang‐1, Tie2, and eNOS, which would increase myocardial capillary density and improve left ventricle function (Azizi et al., 2015). Li et al. also found that apelin‐13 can not only improve the recovery of cardiac function by promoting the upregulation of SDF‐1/CXCR‐4 signaling pathways and vascular progenitor (PC) homing, but also increase the formation of blood vessels in myocardial infarction by upregulating Sirt3 (L. Li et al., 2012; L. Li, Zeng, Hou, He, & Chen, 2013). Recently, researchers have also discovered some new mechanisms of apelin against myocardial infarction. For example: apelin reduces myocardial infarction‐induced fibrosis by inhibiting NF‐κB signaling (Zhang et al., 2015), maintains cell‐ligation integrity by regulating S1P secretion in lymphatic ECs (Tatin et al., 2017), as well as blocks mitochondrial division‐mediated cell death by inhibiting p‐Drp1Ser616 (Xu et al., 2017). Therefore, all these results indicate that apelin is expected to be a marker and therapeutic target for myocardial infarction.

4. DRUGS TARGETING TO APELIN/APJ SYSTEM

At present, some agonists and antagonists of APJ receptors have been discovered and synthesized, and have shown certain therapeutic effects in animal models and patients. Iturrioz et al. (2010) screened out the first nonpeptide APJ receptor agonist‐E339‐3D6. Later, some other APJ agonists such as ML233, MM07, and CMF‐019 were discovered and synthesized one after another (Brame et al., 2015; Khan et al., 2010; Trifonov, Afri, Palczewski, Korshin, & Gruzman, 2018). At the same time, research work on APJ antagonists has been deepening. F13A, as a natural antagonist isoforms of APJ, was found by Lee et al. (2005). By using a bivalent ligand approach, Macaluso, Pitkin, Maguire, Davenport, and Glen (2011) discovered a novel APJ antagonist MM54. Moreover, other antagonists, like ML221 and puerarin have been found by other scientists (Le Gonidec et al., 2017; Maloney et al., 2012). It is worth mentioning that our team has recently conducted a related review of APJ receptor drugs (Huang, He, Chen & Chen, 2018). Therefore, it is foreseeable that apelin agonists and antagonists will continue to emerge, which provides a new way for apelin to treat these endothelial dysfunction‐related diseases.

5. CONCLUSION AND PROSPECTION

In this review, we summarize the link between apelin and EC dysfunction‐related diseases. Interestingly, we find that the apelin/APJ system has a dual role in embryonic development, physiological state, or pathological state. The reasons may be related to factors such as different apelin fragments, types of APJ receptors, complex network signal regulation system, experimental model, dose, and route of administration and so on. Therefore, we can choose the apelin/APJ system drugs to treat EC dysfunction‐related diseases. For example, the antagonist of the APJ receptor is used to treat diabetic retinopathy or tumor angiogenesis, whereas the agonist of the APJ receptor is used to treat hypertension or atherosclerosis. In addition, researchers are constantly trying to find and develop new drugs for the APJ receptor. These above indicate that apelin/APJ system has gradually become a new drug target for the treatment of EC dysfunction‐related diseases, which will receive more and more attention in the future.

CONFLICTS OF INTEREST

The authors declare that there are no conflicts of interest.

ACKNOWLEDGMENTS

This study was supported by grants from the National Natural Science Foundation of China (grant no. 81470434).

Contributor Information

Zhen Huang, Email: huangzhenfy@126.com.

Linxi Chen, Email: lxchen6@126.com.

References

REFERENCES

  1. Akcılar, R. , Turgut, S. , Caner, V. , Akcılar, A. , Ayada, C. , Elmas, L. , & Özcan, T. O. (2013). Apelin effects on blood pressure and RAS in DOCA‐salt‐induced hypertensive rats. Clinical and Experimental Hypertension, 35(7), 550–557. [DOI] [PubMed] [Google Scholar]
  2. Azizi, Y. , Faghihi, M. , Imani, A. , Roghani, M. , & Nazari, A. (2013). Post‐infarct treatment with [Pyr1]‐apelin‐13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction. Peptides, 46, 76–82. [DOI] [PubMed] [Google Scholar]
  3. Azizi, Y. , Faghihi, M. , Imani, A. , Roghani, M. , Zekri, A. , Mobasheri, M. B. , … Moghimian, M. (2015). Post‐infarct treatment with [Pyr(1)]apelin‐13 improves myocardial function by increasing neovascularization and overexpression of angiogenic growth factors in rats. European Journal of Pharmacology, 761, 101–108. [DOI] [PubMed] [Google Scholar]
  4. Berta, J. , Hoda, M. A. , Laszlo, V. , Rozsas, A. , Garay, T. , Torok, S. , … Dome, B. (2014). Apelin promotes lymphangiogenesis and lymph node metastasis. Oncotarget, 5(12), 4426–4437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berta, J. , Kenessey, I. , Dobos, J. , Tovari, J. , Klepetko, W. , Jan Ankersmit, H. , … Dome, B. (2010). Apelin expression in human non‐small cell lung cancer: Role in angiogenesis and prognosis. Journal of Thoracic Oncology, 5(8), 1120–1129. [DOI] [PubMed] [Google Scholar]
  6. Bertero, T. , Lu, Y. , Annis, S. , Hale, A. , Bhat, B. , Saggar, R. , … Chan, S. Y. (2014). Systems‐level regulation of microRNA networks by miR‐130/301 promotes pulmonary hypertension. The Journal of Clinical Investigation, 124(8), 3514–3528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Besserer‐Offroy, É. , Bérubé, P. , Côté, J. , Murza, A. , Longpré, J. M. , Dumaine, R. , … P, P. (2018). The hypotensive effect of activated apelin receptor is correlated with β‐arrestin recruitment. Pharmacological Research, 131, 7–16. [DOI] [PubMed] [Google Scholar]
  8. Bilir, B. , Ekiz Bilir, B. , Yilmaz, I. , Soysal Atile, N. , Yildirim, T. , Kara, S. P. , … Aydin, M. (2016). Association of apelin, endoglin and endocan with diabetic peripheral neuropathy in type 2 diabetic patients. European Review for Medical and Pharmacological Sciences, 20(5), 892–898. [PubMed] [Google Scholar]
  9. Bonetti, P. O. , Lerman, L. O. , & Lerman, A. (2003). Endothelial dysfunction: A marker of atherosclerotic risk. Arteriosclerosis, Thrombosis, and Vascular Biology, 23(2), 168–175. [DOI] [PubMed] [Google Scholar]
  10. Boucher, J. , Masri, B. , Daviaud, D. , Gesta, S. , Guigné, C. , Mazzucotelli, A. , … Valet, P. (2005). Apelin, a newly identified adipokine up‐regulated by insulin and obesity. Endocrinology, 146(4), 1764–1771. [DOI] [PubMed] [Google Scholar]
  11. Brame, A. L. , Maguire, J. J. , Yang, P. , Dyson, A. , Torella, R. , Cheriyan, J. , … Davenport, A. P. (2015). Design, characterization, and first‐in‐human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension, 65(4), 834–840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Busch, R. , Strohbach, A. , Pennewitz, M. , Lorenz, F. , Bahls, M. , Busch, M. C. , & Felix, S. B. (2015). Regulation of the endothelial apelin/APJ system by hemodynamic fluid flow. Cellular Signalling, 27(7), 1286–1296. [DOI] [PubMed] [Google Scholar]
  13. Castan‐Laurell, I. , Vítkova, M. , Daviaud, D. , Dray, C. , Kováčiková, M. , Kovacova, Z. , … Valet, P. (2008). Effect of hypocaloric diet‐induced weight loss in obese women on plasma apelin and adipose tissue expression of apelin and APJ. European Journal of Endocrinology, 158(6), 905–910. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chaves‐Almagro, C. , Castan‐Laurell, I. , Dray, C. , Knauf, C. , Valet, P. , & Masri, B. (2015). Apelin receptors: From signaling to antidiabetic strategy. European Journal of Pharmacologyt, 763, 149–159. [DOI] [PubMed] [Google Scholar]
  15. Chen, D. , Lee, J. , Gu, X. , Wei, L. , & Yu, S. P. (2015). Intranasal delivery of apelin‐13 is neuroprotective and promotes angiogenesis after ischemic stroke in mice. ASN Neuro, 7, 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Chen, H. , Li, J. , Jiao, L. , Petersen, R. B. , Li, J. , Peng, A. , … K., K. (2014). Apelin inhibits the development of diabetic nephropathy by regulating histone acetylation in Akita mouse. Journal of Physiology, 592(3), 505–521. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chen, L. , Tao, Y. , Feng, J. , & Jiang, Y. R. (2015). Apelin protects primary rat retinal pericytes from chemical hypoxia‐induced apoptosis. Journal of Ophthalmology, 2015, 186946–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chng, S. C. , Ho, L. , Tian, J. , & Reversade, B. (2013). ELABELA: A hormone essential for heart development signals via the apelin receptor. Developmental Cell, 27(6), 672–680. [DOI] [PubMed] [Google Scholar]
  19. Chun, H. J. , Ali, Z. A. , Kojima, Y. , Kundu, R. K. , Sheikh, A. Y. , Agrawal, R. , … Quertermous, T. (2008). Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. The Journal of Clinical Investigation, 118(10), 3343–3354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Chun, H. J. , Ali, Z. A. , Kojima, Y. , Kundu, R. K. , Sheikh, A. Y. , Agrawal, R. , … Quertermous, T. (2008). Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. The Journal of Clinical Investigation, 118(10), 3343–3354. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Cox, C. M. , D'Agostino, S. L. , Miller, M. K. , Heimark, R. L. , & Krieg, P. A. (2006). Apelin, the ligand for the endothelial G‐protein‐coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Developmental Biology, 296(1), 177–189. [DOI] [PubMed] [Google Scholar]
  22. Dray, C. , Debard, C. , Jager, J. , Disse, E. , Daviaud, D. , Martin, P. , … Castan‐Laurell, I. (2010). Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans. American Journal of Physiology: Endocrinology and Metabolism, 298(6), E1161–E1169. [DOI] [PubMed] [Google Scholar]
  23. Dray, C. , Knauf, C. , Daviaud, D. , Waget, A. , Boucher, J. , Buléon, M. , … Valet, P. (2008). Apelin stimulates glucose utilization in normal and obese insulin‐resistant mice. Cell Metabolism, 8(5), 437–445. [DOI] [PubMed] [Google Scholar]
  24. Du, J. H. , Li, X. , Li, R. , Xu, L. , Ma, R. R. , Liu, S. F. , … Sun, H. Z. (2014). Elevation of serum apelin‐13 associated with proliferative diabetic retinopathy in type 2 diabetic patients. International Journal of Ophthalmology, 7(6), 968–973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Erdem, G. , Dogru, T. , Tasci, I. , Sonmez, A. , & Tapan, S. (2008). Low plasma apelin levels in newly diagnosed type 2 diabetes mellitus. Experimental and Clinical Endocrinology & Diabetes, 116(5), 289–292. [DOI] [PubMed] [Google Scholar]
  26. Eyries, M. , Siegfried, G. , Ciumas, M. , Montagne, K. , Agrapart, M. , Lebrin, F. , & Soubrier, F. (2008). Hypoxia‐induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circulation Research, 103(4), 432–440. [DOI] [PubMed] [Google Scholar]
  27. Fukuda, S. , Kaga, S. , Sasaki, H. , Zhan, L. , Zhu, L. , Otani, H. , … Maulik, N. (2004). Angiogenic signal triggered by ischemic stress induces myocardial repair in rat during chronic infarction. Journal of Molecular and Cellular Cardiology, 36(4), 547–559. [DOI] [PubMed] [Google Scholar]
  28. Le Gonidec, S. , Chaves‐Almagro, C. , Bai, Y. , Kang, H. J. , Smith, A. , Wanecq, E. , … Masri, B. (2017). Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin. FASEB Journal, 31(6), 2507–2519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Guo, C. , Liu, Y. , Zhao, W. , Wei, S. , Zhang, X. , Wang, W. , & Zeng, X. (2015). Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities. Journal of Cellular and Molecular Medicine, 19(9), 2273–2285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Guo, S. , Yu, L. , Cheng, Y. , Li, C. , Zhang, J. , An, J. , … Li, Z. (2012). PDGFRbeta triggered by bFGF promotes the proliferation and migration of endothelial progenitor cells via p‐ERK signalling. Cell Biology International, 36(10), 945–950. [DOI] [PubMed] [Google Scholar]
  31. Hashimoto, T. , Kihara, M. , Imai, N. , Yoshida, S. , Shimoyamada, H. , Yasuzaki, H. , … Umemura, S. (2007). Requirement of apelin‐apelin receptor system for oxidative stress‐linked atherosclerosis. The American Journal of Pathology, 171(5), 1705–1712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Helenius, M. H. , Vattulainen, S. , Orcholski, M. , Aho, J. , Komulainen, A. , Taimen, P. , … Alastalo, T. P. (2015). Suppression of endothelial CD39/ENTPD1 is associated with pulmonary vascular remodeling in pulmonary arterial hypertension. American Journal of Physiology Lung Cellular and Molecular Physiology, 308(10), L1046–L1057. [DOI] [PubMed] [Google Scholar]
  33. Helker, C. S. , Schuermann, A. , Pollmann, C. , Chng, S. C. , Kiefer, F. , Reversade, B. , & Herzog, W. (2015). The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis. eLife, 4, 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hou, J. , Zhong, T. , Guo, T. , Miao, C. , Zhou, C. , Long, H. , … Wang, T. (2017). Apelin promotes mesenchymal stem cells survival and vascularization under hypoxic‐ischemic condition in vitro involving the upregulation of vascular endothelial growth factor. Experimental and Molecular Pathology, 102(2), 203–209. [DOI] [PubMed] [Google Scholar]
  35. Hou, X. , Zeng, H. , He, X. , & Chen, J. X. (2015). Sirt3 is essential for apelin‐induced angiogenesis in post‐myocardial infarction of diabetes. Journal of Cellular and Molecular Medicine, 19(1), 53–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Huang, Z. , He, L. , Chen, Z. , & Chen, L. (2018). Targeting drugs to APJ receptor: From signaling to pathophysiological effects. Journal of Cellular Physiology, 234(1), 61–74. [DOI] [PubMed] [Google Scholar]
  37. Ishida, J. , Hashimoto, T. , Hashimoto, Y. , Nishiwaki, S. , Iguchi, T. , Harada, S. , … Fukamizu, A. (2004). Regulatory roles for APJ, a seven‐transmembrane receptor related to angiotensin‐type 1 receptor in blood pressure in vivo. The Journal of Biological Chemistry, 279(25), 26274–26279. [DOI] [PubMed] [Google Scholar]
  38. Ishimaru, Y. , Shibagaki, F. , Yamamuro, A. , Yoshioka, Y. , & Maeda, S. (2017). An apelin receptor antagonist prevents pathological retinal angiogenesis with ischemic retinopathy in mice. Scientific Reports, 7(1), 15062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Iturrioz, X. , Alvear‐Perez, R. , De Mota, N. , Franchet, C. , Guillier, F. , Leroux, V. , … Llorens‐Cortes, C. (2010). Identification and pharmacological properties of E339‐3D6, the first nonpeptidic apelin receptor agonist. FASEB Journal, 24(5), 1506–1517. [DOI] [PubMed] [Google Scholar]
  40. Jia, Y. X. , Lu, Z. F. , Zhang, J. , Pan, C. S. , Yang, J. H. , Zhao, J. , … YF., Y. F. (2007). Apelin activates L‐arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Peptides, 28(10), 2023–2029. [DOI] [PubMed] [Google Scholar]
  41. Jin, W. , Su, X. , Xu, M. , Liu, Y. , Shi, J. , Lu, L. , & W., W. (2012). Interactive association of five candidate polymorphisms in Apelin/APJ pathway with coronary artery disease among Chinese hypertensive patients. PLOS One, 7(12), e51123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kadoglou, N. P. E. , Sailer, N. , Moumtzouoglou, A. , Kapelouzou, A. , Gerasimidis, T. , Kostakis, A. , & Liapis, C. D. (2012). Adipokines: A novel link between adiposity and carotid plaque vulnerability. European Journal of Clinical Investigation, 42(12), 1278–1286. [DOI] [PubMed] [Google Scholar]
  43. Kadoglou, N. P. E. , Tsanikidis, H. , Kapelouzou, A. , Vrabas, I. , Vitta, I. , Karayannacos, P. E. , … Sailer, N. (2010). Effects of rosiglitazone and metformin treatment on apelin, visfatin, and ghrelin levels in patients with type 2 diabetes mellitus. Metabolism: Clinical and Experimental, 59(3), 373–379. [DOI] [PubMed] [Google Scholar]
  44. Kapica, M. , Jankowska, A. , Antushevich, H. , Pietrzak, P. , Bierla, J. B. , Dembinski, A. , & Zabielski, R. (2012). The effect of exogenous apelin on the secretion of pancreatic juice in anaesthetized rats. Journal of Physiology and Pharmacology, 63(1), 53–60. [PubMed] [Google Scholar]
  45. Kasai, A. , Ishimaru, Y. , Higashino, K. , Kobayashi, K. , Yamamuro, A. , Yoshioka, Y. , & Maeda, S. (2013). Inhibition of apelin expression switches endothelial cells from proliferative to mature state in pathological retinal angiogenesis. Angiogenesis, 16(3), 723–734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Kasai, A. , Ishimaru, Y. , Kinjo, T. , Satooka, T. , Matsumoto, N. , Yoshioka, Y. , … Maeda, S. (2010). Apelin is a crucial factor for hypoxia‐induced retinal angiogenesis. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(11), 2182–2187. [DOI] [PubMed] [Google Scholar]
  47. Kasai, A. , Shintani, N. , Kato, H. , Matsuda, S. , Gomi, F. , Haba, R. , … Baba, A. (2008). Retardation of retinal vascular development in apelin‐deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(10), 1717–1722. [DOI] [PubMed] [Google Scholar]
  48. Kasai, A. , Shintani, N. , Oda, M. , Kakuda, M. , Hashimoto, H. , Matsuda, T. , … Baba, A. (2004). Apelin is a novel angiogenic factor in retinal endothelial cells. Biochemical and Biophysical Research Communications, 325(2), 395–400. [DOI] [PubMed] [Google Scholar]
  49. Khan, P , Maloney, PR , Hedrick, M , Gosalia, P , Milewski, M , Li, L , … Smith, LH. 2010. Functional agonists of the apelin (APJ) receptor. Probe Reports from the NIH Molecular Libraries Program, Bethesda, MD.
  50. Kidoya, H. , Ueno, M. , Yamada, Y. , Mochizuki, N. , Nakata, M. , Yano, T. , … Takakura, N. (2008). Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. The EMBO Journal, 27(3), 522–534. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Kim, J. , Kang, Y. , Kojima, Y. , Lighthouse, J. K. , Hu, X. , Aldred, M. A. , … Chun, H. J. (2013). An endothelial apelin‐FGF link mediated by miR‐424 and miR‐503 is disrupted in pulmonary arterial hypertension. Nature Medicine, 19(1), 74–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Kleinz, M. J. , & Davenport, A. P. (2004). Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regulatory Peptides, 118(3), 119–125. [DOI] [PubMed] [Google Scholar]
  53. Ko, S. H. , & Bandyk, D. F. (2014). Therapeutic angiogenesis for critical limb ischemia. Seminars in Vascular Surgery, 27(1), 23–31. [DOI] [PubMed] [Google Scholar]
  54. Kolluru, G. K. , Bir, S. C. , & Kevil, C. G. (2012). Endothelial dysfunction and diabetes: Effects on angiogenesis, vascular remodeling, and wound healing. International Journal of Vascular Medicine, 2012, 918267–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Kostopoulos, C. G. , Spiroglou, S. G. , Varakis, J. N. , Apostolakis, E. , & Papadaki, H. H. (2014). Adiponectin/T‐cadherin and apelin/APJ expression in human arteries and periadventitial fat: Implication of local adipokine signaling in atherosclerosis? Cardiovascular Pathology, 23(3), 131–138. [DOI] [PubMed] [Google Scholar]
  56. Kourtis, A. , Gkiomisi, A. , Mouzaki, M. , Makedou, K. , Anastasilakis, A. D. , Toulis, K. A. , … Agorastos, T. (2011). Apelin levels in normal pregnancy. Clinical Endocrinology, 75(3), 367–371. [DOI] [PubMed] [Google Scholar]
  57. Kunduzova, O. , Alet, N. , Delesque‐Touchard, N. , Millet, L. , Castan‐Laurell, I. , Muller, C. , … Valet, P. (2008). Apelin/APJ signaling system: A potential link between adipose tissue and endothelial angiogenic processes. FASEB Journal, 22(12), 4146–4153. [DOI] [PubMed] [Google Scholar]
  58. Kursunluoglu‐Akcilar, R. , Kilic‐Toprak, E. , Kilic‐Erkek, O. , Turgut, S. , & Bor‐Kucukatay, M. (2014). Apelin‐induced hemorheological alterations in DOCA‐salt hypertensive rats. Clinical Hemorheology and Microcirculation, 56(1), 75–82. [DOI] [PubMed] [Google Scholar]
  59. Kwon, H. B. , Wang, S. , Helker, C. S. M. , Rasouli, S. J. , Maischein, H. M. , Offermanns, S. , … Stainier, D. Y. R. (2016). In vivo modulation of endothelial polarization by Apelin receptor signalling. Nature Communications, 7, 11805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Kälin, R. E. , Kretz, M. P. , Meyer, A. M. , Kispert, A. , Heppner, F. L. , & Brändli, A. W. (2007). Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Developmental Biology, 305(2), 599–614. [DOI] [PubMed] [Google Scholar]
  61. Lee, D. K. , Cheng, R. , Nguyen, T. , Fan, T. , Kariyawasam, A. P. , Liu, Y. , … O’Dowd, B. F. (2000). Characterization of apelin, the ligand for the APJ receptor. Journal of Neurochemistry, 74(1), 34–41. [DOI] [PubMed] [Google Scholar]
  62. Lee, D. K. , Saldivia, V. R. , Nguyen, T. , Cheng, R. , George, S. R. , & O’dowd, B. F. (2005). Modification of the terminal residue of apelin‐13 antagonizes its hypotensive action. Endocrinology, 146(1), 231–236. [DOI] [PubMed] [Google Scholar]
  63. Li, L. , Zeng, H. , & Chen, J. X. (2012). Apelin‐13 increases myocardial progenitor cells and improves repair postmyocardial infarction. American Journal of Physiology Heart and Circulatory Physiology, 303(5), H605–H618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Li, L. , Zeng, H. , Hou, X. , He, X. , & Chen, J. X. (2013). Myocardial injection of apelin‐overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction. PLOS One, 8(9), e71041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Li, W. W. , Niu, W. Q. , Zhang, Y. , Wu, S. , Gao, P. J. , & DL., D. L. (2009). Family‐based analysis of apelin and AGTRL1 gene polymorphisms with hypertension in Han Chinese. Journal of Hypertension, 27(6), 1194–1201. [DOI] [PubMed] [Google Scholar]
  66. Li, X. , Zhang, X. , Li, F. , Chen, L. , Li, L. , Qin, X. , … Liao, D. (2010). 14‐3‐3 mediates apelin‐13‐induced enhancement of adhesion of monocytes to human umbilical vein endothelial cells. Acta Biochimica et Biophysica Sinica, 42(6), 403–409. [DOI] [PubMed] [Google Scholar]
  67. Li, Y. , Bai, Y. , Jiang, Y. , Yu, W. , Shi, X. , Chen, L. , … Sun, G. (2018). Apelin‐13 is an early promoter of cytoskeleton and tight junction in diabetic macular edema via PI‐3K/Akt and MAPK/Erk signaling pathways. BioMed Research International, 2018, 3242574–17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Liu, M. , Li, H. , Zhou, Q. , Zhao, H. , Lv, D. , Cao, J. , … Chen, L. (2018). ROS‐Autophagy pathway mediates monocytes‐human umbilical vein endothelial cells adhesion induced by apelin‐13. Journal of Cellular Physiology, 233(10), 6839–6850. [DOI] [PubMed] [Google Scholar]
  69. Liu, S. , Wang, W. , Yin, L. , & Zhu, Y. (2018). Influence of apelin‐13 on osteoporosis in Type‐2 diabetes mellitus: A clinical study. Pakistan Journal of Medical Sciences, 34(1), 159–163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Liu, X. Y. , Lu, Q. , Ouyang, X. P. , Tang, S. L. , Zhao, G. J. , Lv, Y. C. , … CK., C. K. (2013). Apelin‐13 increases expression of ATP‐binding cassette transporter A1 via activating protein kinase C α signaling in THP‐1 macrophage‐derived foam cells. Atherosclerosis, 226(2), 398–407. [DOI] [PubMed] [Google Scholar]
  71. Liu, Y. , Zhang, J. , Wang, Y. , & Zeng, X. (2017). Apelin involved in progression of diabetic nephropathy by inhibiting autophagy in podocytes. Cell Death & Disease, 8(8), e3006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Lu, Y. , Zhu, X. , Liang, G. X. , Cui, R. R. , Liu, Y. , Wu, S. S. , … Liao, E. Y. (2012). Apelin‐APJ induces ICAM‐1, VCAM‐1 and MCP‐1 expression via NF‐kappaB/JNK signal pathway in human umbilical vein endothelial cells. Amino Acids, 43(5), 2125–2136. [DOI] [PubMed] [Google Scholar]
  73. Luo, X. , Liu, J. , Zhou, H. , & Chen, L. (2018). Apelin/APJ system: A critical regulator of vascular smooth muscle cell. Journal of Cellular Physiology, 233(7), 5180–5188. [DOI] [PubMed] [Google Scholar]
  74. Lv, S. Y. , Yang, Y. J. , & Chen, Q. (2013). Regulation of feeding behavior, gastrointestinal function and fluid homeostasis by apelin. Peptides, 44, 87–92. [DOI] [PubMed] [Google Scholar]
  75. Macaluso, N. J. M. , Pitkin, S. L. , Maguire, J. J. , Davenport, A. P. , & Glen, R. C. (2011). Discovery of a competitive apelin receptor (APJ) antagonist. ChemMedChem, 6(6), 1017–1023. [DOI] [PubMed] [Google Scholar]
  76. Maloney, P. R. , Khan, P. , Hedrick, M. , Gosalia, P. , Milewski, M. , Li, L. , … Pinkerton, A. B. (2012). Discovery of 4‐oxo‐6‐((pyrimidin‐2‐ylthio)methyl)‐4H‐pyran‐3‐yl 4‐nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor. Bioorganic & Medicinal Chemistry Letters, 22(21), 6656–6660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Masri, B. , van den Berghe, L. , Sorli, C. , Knibiehler, B. , & Audigier, Y. (2009). Apelin signalisation and vascular physiopathology. Journal de la Societe de Biologie, 203(2), 171–179. [DOI] [PubMed] [Google Scholar]
  78. Masri, B. , Morin, N. , Cornu, M. , Knibiehler, B. , & Audigier, Y. (2004). Apelin (65‐77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB Journal, 18(15), 1909–1911. [DOI] [PubMed] [Google Scholar]
  79. Najafipour, H. , Vakili, A. , Shahouzehi, B. , Soltani Hekmat, A. , Masoomi, Y. , Yeganeh Hajahmadi, M. , & Esmaeli‐Mahani, S. (2015). Investigation of changes in apelin receptor mRNA and protein expression in the myocardium and aorta of rats with two‐kidney, one‐clip (2K1C) Goldblatt hypertension. Journal of Physiology and Biochemistry, 71(2), 165–175. [DOI] [PubMed] [Google Scholar]
  80. Novakova, V. , Sandhu, G. S. , Dragomir‐Daescu, D. , & Klabusay, M. (2016). Apelinergic system in endothelial cells and its role in angiogenesis in myocardial ischemia. Vascular pharmacology, 76, 1–10. [DOI] [PubMed] [Google Scholar]
  81. Nowzari, Z. , Masoumi, M. , Nazari‐Robati, M. , Akbari, H. , Shahrokhi, N. , & Asadikaram, G. (2018). Association of polymorphisms of leptin, leptin receptor and apelin receptor genes with susceptibility to coronary artery disease and hypertension. Life Sciences, 207, 166–171. [DOI] [PubMed] [Google Scholar]
  82. O’Dowd, B. F. , Heiber, M. , Chan, A. , Heng, H. H. Q. , Tsui, L. C. , Kennedy, J. L. , … Nguyen, T. (1993). A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene, 136(1‐2), 355–360. [DOI] [PubMed] [Google Scholar]
  83. Papadopoulos, D. P. , Mourouzis, I. , Faselis, C. , Perrea, D. , Makris, T. , Tsioufis, C. , & Papademetriou, V. (2013). Masked hypertension and atherogenesis: The impact of apelin and relaxin plasma levels. Journal of Clinical Hypertension, 15(5), 333–336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Patel, C. , Narayanan, S. P. , Zhang, W. , Xu, Z. , Sukumari‐Ramesh, S. , Dhandapani, K. M. , … Caldwell, R. B. (2014). Activation of the endothelin system mediates pathological angiogenesis during ischemic retinopathy. The American Journal of Pathology, 184(11), 3040–3051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Perjés, Á. , Kilpiö, T. , Ulvila, J. , Magga, J. , Alakoski, T. , Szabó, Z. , … R, R. (2016). Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart. Basic Research in Cardiology, 111(1), 2. [DOI] [PubMed] [Google Scholar]
  86. Pi, J. , Cheng, Y. , Sun, H. , Chen, X. , Zhuang, T. , Liu, J. , … Tao, T. (2017). Apln‐CreERT:MT/mG reporter mice as a tool for sprouting angiogenesis study. BMC Ophthalmology, 17(1), 163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Pisarenko, O. I. , Pelogeykina, Y. A. , Bespalova, Z. D. , Serebryakova, L. I. , Sidorova, M. V. , Az’muko, A. A. , … Molokoedov, A. S. (2012). Limitation of myocardial infarction by a structural analog of the peptide apelin‐12. Doklady Biological Sciences, 443, 65–67. [DOI] [PubMed] [Google Scholar]
  88. Pisarenko, O. I. , Serebryakova, L. I. , Pelogeykina, Y. A. , Studneva, I. M. , Khatri, D. N. , Tskitishvili, O. V. , … Pal’keeva, M. E. (2011). In vivo reduction of reperfusion injury to the heart with apelin‐12 peptide in rats. Bulletin of Experimental Biology and Medicine, 152(1), 79–82. [DOI] [PubMed] [Google Scholar]
  89. Plein, A. , Fantin, A. , Denti, L. , Pollard, J. W. , & Ruhrberg, C. (2018). Erythro‐myeloid progenitors contribute endothelial cells to blood vessels. Nature, 562(7726), 223–228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Poirier, O. , Ciumas, M. , Eyries, M. , Montagne, K. , Nadaud, S. , & Soubrier, F. (2012). Inhibition of apelin expression by BMP signaling in endothelial cells. American Journal of Physiology Cell Physiology, 303(11), C1139–C1145. [DOI] [PubMed] [Google Scholar]
  91. Qin, D. , Zheng, X. X. , & Jiang, Y. R. (2013). Apelin‐13 induces proliferation, migration, and collagen I mRNA expression in human RPE cells via PI3K/Akt and MEK/Erk signaling pathways. Molecular Vision, 19, 2227–2236. [PMC free article] [PubMed] [Google Scholar]
  92. Rastaldo, R. , Cappello, S. , Folino, A. , Berta, G. N. , Sprio, A. E. , Losano, G. , … Pagliaro, P. (2011). Apelin‐13 limits infarct size and improves cardiac postischemic mechanical recovery only if given after ischemia. American Journal of Physiology: Heart and Circulatory Physiology, 300(6), H2308–H2315. [DOI] [PubMed] [Google Scholar]
  93. Ringström, C. , Nitert, M. D. , Bennet, H. , Fex, M. , Valet, P. , Rehfeld, J. F. , … Wierup, N. (2010). Apelin is a novel islet peptide. Regulatory Peptides, 162(1–3), 44–51. [DOI] [PubMed] [Google Scholar]
  94. Rittig, K. , Hildebrandt, U. , Thamer, C. , Staiger, H. , Peter, A. , Stefan, N. , … Siegel‐Axel, D. (2011). Apelin serum levels are not associated with early atherosclerosis or fat distribution in young subjects with increased risk for type 2 diabetes. Experimental and Clinical Endocrinology & Diabetes, 119(6), 358–361. [DOI] [PubMed] [Google Scholar]
  95. Ronkainen, V. P. , Ronkainen, J. J. , Hänninen, S. L. , Leskinen, H. , Ruas, J. L. , Pereira, T. , … Tavi, P. (2007). Hypoxia inducible factor regulates the cardiac expression and secretion of apelin. FASEB Journal, 21(8), 1821–1830. [DOI] [PubMed] [Google Scholar]
  96. Samareh Fekri, M. , Etminan, A. , Rashidnedjad, A. , Mojibian, A. , & Masoomi, Y. (2018). Serum apelin peptide level in hemodialysis patients with pulmonary arterial hypertension. Iranian Journal of Kidney Disease, 12(4), 209–214. [PubMed] [Google Scholar]
  97. Sans‐Roselló, J. , Casals, G. , Rossello, X. , González de la presa, B. , Vila, M. , Duran‐Cambra, A. , … Sionis, A. (2017). Prognostic value of plasma apelin concentrations at admission in patients with ST‐segment elevation acute myocardial infarction. Clinical Biochemistry, 50(6), 279–284. [DOI] [PubMed] [Google Scholar]
  98. Sheikh, A. Y. , Chun, H. J. , Glassford, A. J. , Kundu, R. K. , Kutschka, I. , Ardigo, D. , … Quertermous, T. (2008). In vivo genetic profiling and cellular localization of apelin reveals a hypoxia‐sensitive, endothelial‐centered pathway activated in ischemic heart failure. American Journal of Physiology Heart and Circulatory Physiology, 294(1), H88–H98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Shen, Y. H. , Shoichet, M. S. , & Radisic, M. (2008). Vascular endothelial growth factor immobilized in collagen scaffold promotes penetration and proliferation of endothelial cells. Acta Biomaterialia, 4(3), 477–489. [DOI] [PubMed] [Google Scholar]
  100. Shi, H. , Yuan, L. , Yang, H. , & Zang, A. (2017). The mechanism of all‐trans retinoic acid in the regulation of apelin expression in vascular endothelial cells. Bioscience Reports, 37, 6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Soriguer, F. , Garrido‐Sanchez, L. , Garcia‐Serrano, S. , Garcia‐Almeida, J. M. , Garcia‐Arnes, J. , Tinahones, F. J. , & Garcia‐Fuentes, E. (2009). Apelin levels are increased in morbidly obese subjects with type 2 diabetes mellitus. Obesity Surgery, 19(11), 1574–1580. [DOI] [PubMed] [Google Scholar]
  102. Strohbach, A. , Pennewitz, M. , Glaubitz, M. , Palankar, R. , Groß, S. , Lorenz, F. , … Busch, R. (2018). The apelin receptor influences biomechanical and morphological properties of endothelial cells. Journal of Cellular Physiology, 233(8), 6250–6261. [DOI] [PubMed] [Google Scholar]
  103. Stöhr, R. , Kappel, B. A. , Carnevale, D. , Cavalera, M. , Mavilio, M. , Arisi, I. , … Federici, M. (2015). TIMP3 interplays with apelin to regulate cardiovascular metabolism in hypercholesterolemic mice. Molecular Metabolism, 4(10), 741–752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Takakura, N. , & Kidoya, H. (2009). Maturation of blood vessels by haematopoietic stem cells and progenitor cells: Involvement of apelin/APJ and angiopoietin/Tie2 interactions in vessel caliber size regulation. Thrombosis and Haemostasis, 101(6), 999–1005. [PubMed] [Google Scholar]
  105. Tao, Y. , Lu, Q. , Jiang, Y. R. , Qian, J. , Wang, J. Y. , Gao, L. , & Jonas, J. B. (2010). Apelin in plasma and vitreous and in fibrovascular retinal membranes of patients with proliferative diabetic retinopathy. Investigative Ophthalmology & Visual Science, 51(8), 4237–4242. [DOI] [PubMed] [Google Scholar]
  106. Tasci, I. , Dogru, T. , Naharci, I. , Erdem, G. , Yilmaz, M. I. , Sonmez, A. , … Erikci, S. (2007). Plasma apelin is lower in patients with elevated LDL‐cholesterol. Experimental and Clinical Endocrinology & Diabetes, 115(7), 428–432. [DOI] [PubMed] [Google Scholar]
  107. Tatemoto, K. , Hosoya, M. , Ryo, Fujii , Habata, Y. , Fujii, R. , Kakegawa, T. , Zou, M. X. , … Fujino, M. (1998). Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochemical and Biophysical Research Communications, 251, 471–476. [DOI] [PubMed] [Google Scholar]
  108. Tatemoto, K. , Takayama, K. , Zou, M. X. , Kumaki, I. , Zhang, W. , Kumano, K. , & M., M. (2001). The novel peptide apelin lowers blood pressure via a nitric oxide‐dependent mechanism. Regulatory Peptides, 99(2‐3), 87–92. [DOI] [PubMed] [Google Scholar]
  109. Tatin, F. , Renaud‐Gabardos, E. , Godet, A. C. , Hantelys, F. , Pujol, F. , Morfoisse, F. , … Garmy‐Susini, B. (2017). Apelin modulates pathological remodeling of lymphatic endothelium after myocardial infarction. JCI Insight, 2, 12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Tiani, C. , Garcia‐Pras, E. , Mejias, M. , de Gottardi, A. , Berzigotti, A. , Bosch, J. , & Fernandez, M. (2009). Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension. Journal of Hepatology, 50(2), 296–305. [DOI] [PubMed] [Google Scholar]
  111. del Toro, R. , Prahst, C. , Mathivet, T. , Siegfried, G. , Kaminker, J. S. , Larrivee, B. , … Eichmann, A. (2010). Identification and functional analysis of endothelial tip cell‐enriched genes. Blood, 116(19), 4025–4033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Trifonov, L. , Afri, M. , Palczewski, K. , Korshin, E. E. , & Gruzman, A. (2018). An expedient synthesis of CMF‐019: (S)‐5‐methyl‐3‐{1‐(pentan‐3yl)‐2‐(thiophen‐2‐ylmethyl)‐1H‐benzo[d]imidazole‐5‐carboxamido}hexanoic acid, a potent apelin receptor (APJ) agonist. Medicinal Chemistry, 14(7), 688–694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Visser, Y. P. , Walther, F. J. , Laghmani, E. H. , Laarse, A. , & Wagenaar, G. T. M. (2010). Apelin attenuates hyperoxic lung and heart injury in neonatal rats. American Journal of Respiratory and Critical Care Medicine, 182(10), 1239–1250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Wang, W. , McKinnie, S. M. K. , Patel, V. B. , Haddad, G. , Wang, Z. , Zhabyeyev, P. , … Oudit, G. Y. (2013). Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia‐reperfusion injury: Therapeutic potential of synthetic Apelin analogues. Journal of the American Heart Association, 2(4), e000249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Wang, Z. , Yu, D. , Wang, M. , Wang, Q. , Kouznetsova, J. , Yang, R. , … Gong, D. W. (2015). Elabela‐apelin receptor signaling pathway is functional in mammalian systems. Scientific Reports, 5, 8170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Weir, R. A. P. , Chong, K. S. , Dalzell, J. R. , Petrie, C. J. , Murphy, C. A. , Steedman, T. , … McMurray, J. J. V. (2009). Plasma apelin concentration is depressed following acute myocardial infarction in man. European Journal of Heart Failure, 11(6), 551–558. [DOI] [PubMed] [Google Scholar]
  117. Welén, K. , Jennbacken, K. , Tes̆an, T. , & Damber, J. E. (2009). Pericyte coverage decreases invasion of tumour cells into blood vessels in prostate cancer xenografts. Prostate Cancer and Prostatic Diseases, 12(1), 41–46. [DOI] [PubMed] [Google Scholar]
  118. Wen, Y. , Chen, R. , Zhu, C. , Qiao, H. , Liu, Y. , Ji, H. , … Yang, Y. (2018). MiR‐503 suppresses hypoxia‐induced proliferation, migration and angiogenesis of endothelial progenitor cells by targeting Apelin. Peptides, 105, 58–65. [DOI] [PubMed] [Google Scholar]
  119. Xu, W. , Yu, H. , Ma, R. , Ma, L. , Liu, Q. , Shan, H. , … Shan, H. (2017). Apelin protects against myocardial ischemic injury by inhibiting dynamin‐related protein 1. Oncotarget, 8(59), 100034–100044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  120. Yang, B. R. , Cheung, K. K. , Zhou, X. , Xie, R. F. , Cheng, P. P. , Wu, S. , … Lee, S. M. Y. (2016). Amelioration of acute myocardial infarction by saponins from flower buds of Panax notoginseng via pro‐angiogenesis and anti‐apoptosis. Journal of Ethnopharmacology, 181, 50–58. [DOI] [PubMed] [Google Scholar]
  121. Yang, X. , Zhu, W. , Zhang, P. , Chen, K. , Zhao, L. , Li, J. , … Liu, M. (2014). Apelin‐13 stimulates angiogenesis by promoting crosstalk between AMP‐activated protein kinase and Akt signaling in myocardial microvascular endothelial cells. Molecular Medicine Reports, 9(5), 1590–1596. [DOI] [PubMed] [Google Scholar]
  122. Yao, F. , Lv, Y. C. , Zhang, M. , Xie, W. , Tan, Y. L. , Gong, D. , … Tang, C. K. (2015). Apelin‐13 impedes foam cell formation by activating Class III PI3K/Beclin‐1‐mediated autophagic pathway. Biochemical and Biophysical Research Communications, 466(4), 637–643. [DOI] [PubMed] [Google Scholar]
  123. Ye, L. , Ding, F. , Zhang, L. , Shen, A. , Yao, H. , Deng, L. , & Ding, Y. (2015). Serum apelin is associated with left ventricular hypertrophy in untreated hypertension patients. Journal of Translational Medicine, 13, 290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Yeganeh‐Hajahmadi, M. , Najafipour, H. , & Rostamzadeh, F. (2017). The differential effects of low and high doses of apelin through opioid receptors on the blood pressure of rats with renovascular hypertension. Hypertension Research, 40(8), 732–737. [DOI] [PubMed] [Google Scholar]
  125. Yue, P. J. H. , illaud‐Manzanera, M. , Deng, A. C. , Azuma, J. , Asagami, T. , Kundu, R. K. , … Tsao, P. S. (2010). Apelin is necessary for the maintenance of insulin sensitivity. American Journal of Physiology: Endocrinology and Metabolism, 298, 1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  126. Zeng, H. , He, X. , Hou, X. , Li, L. , & Chen, J. X. (2014). Apelin gene therapy increases myocardial vascular density and ameliorates diabetic cardiomyopathy via upregulation of sirtuin 3. American Journal of Physiology Heart and Circulatory Physiology, 306(4), H585–H597. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Zeng, X. J. , Zhang, L. K. , Wang, H. X. , Lu, L. Q. , Ma, L. Q. , & Tang, C. S. (2009). Apelin protects heart against ischemia/reperfusion injury in rat. Peptides, 30(6), 1144–1152. [DOI] [PubMed] [Google Scholar]
  128. Zhang, B. H. , Wang, W. , Wang, H. , Yin, J. , & Zeng, X. (2013). Promoting effects of the adipokine, apelin, on diabetic nephropathy. PLOS One, 8(4), e60457. [DOI] [PMC free article] [PubMed] [Google Scholar]
  129. Zhang, F. , Sun, H. J. , Xiong, X. Q. , Chen, Q. , Li, Y. H. , Kang, Y. M. , … Zhu, G. Q. (2014). Apelin‐13 and APJ in paraventricular nucleus contribute to hypertension via sympathetic activation and vasopressin release in spontaneously hypertensive rats. Acta physiologica, 212(1), 17–27. [DOI] [PubMed] [Google Scholar]
  130. Zhang, J. , Liu, Q. , Fang, Z. , Hu, X. , Huang, F. , Tang, L. , & Zhou, S. (2016). Hypoxia induces the proliferation of endothelial progenitor cells via upregulation of Apelin/APLNR/MAPK signaling. Molecular Medicine Reports, 13(2), 1801–1806. [DOI] [PubMed] [Google Scholar]
  131. Zhang, J. , Liu, Q. , Hu, X. , Fang, Z. , Huang, F. , Tang, L. , & Zhou, S. (2015). Apelin/APJ signaling promotes hypoxia‐induced proliferation of endothelial progenitor cells via phosphoinositide‐3 kinase/Akt signaling. Molecular Medicine Reports, 12(3), 3829–3834. [DOI] [PubMed] [Google Scholar]
  132. Zhang, J. , Yin, J. , Wang, Y. , Li, B. , & Zheng, X. (2018). Apelin impairs myogenic response to induce diabetic nephropathy in mice. FASEB Journal, 32(8), 4315–4327. [DOI] [PubMed] [Google Scholar]
  133. Zhang, Q. , Yao, F. , Raizada, M. K. , O’Rourke, S. T. , & Sun, C. (2009). Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. Circulation Research, 104(12), 1421–1428. [DOI] [PMC free article] [PubMed] [Google Scholar]
  134. Zhang, X. , Ye, Q. , Gong, D. , Lv, Y. , Cheng, H. , Huang, C. , … Tang, C. (2009). Apelin‐13 inhibits lipoprotein lipase expression via the APJ/PKCα/miR‐361‐5p signaling pathway in THP‐1 macrophage‐derived foam cells. Acta Biochimica et Biophysica Sinica, 49(6), 530–540. [DOI] [PubMed] [Google Scholar]
  135. Zhao, H. , Yao, P. , Li, L. , & Chen, L. (2016). Apelin receptor signaling: A novel mechanism of endothelial cell polarization. Acta Biochimica et Biophysica Sinica, 48(12), 1138–1139. [DOI] [PubMed] [Google Scholar]
  136. Zhong, J. C. , Yu, X. Y. , Huang, Y. , Yung, L. M. , Lau, C. W. , & Lin, S. G. (2007). Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovascular Research, 74(3), 388–395. [DOI] [PubMed] [Google Scholar]
  137. Zhou, Y. , Wang, Y. , & Qiao, S. (2014). Apelin: A potential marker of coronary artery stenosis and atherosclerotic plaque stability in ACS patients. International Heart Journal, 55(3), 204–212. [DOI] [PubMed] [Google Scholar]
  138. Zhu, S. , Sun, F. , Li, W. , Cao, Y. , Wang, C. , Wang, Y. , … Cao, F. (2011). Apelin stimulates glucose uptake through the PI3K/Akt pathway and improves insulin resistance in 3T3‐L1 adipocytes. Molecular and Cellular Biochemistry, 353(1–2), 305–313. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Cellular Physiology are provided here courtesy of Wiley

RESOURCES