The apelin receptor (AR or APJ) is a class A, rhodopsin-like G protein-coupled receptor, which shares closest homology to the angiotensin II type 1 receptor (AT1). Despite this homology, it does not bind angiotensin II.
The human apelin receptor consists of 380 amino acids. It shares a similar tissue distribution with its endogenous ligand apelin indicating that apelin acts as a paracrine/autocrine mediator. Immunocytochemical detection of the human apelin receptor localized it to cardiomyocytes, vascular smooth muscle and endothelial cells.
The apelin receptor is thought to signal primarily through GαI, leading to decreased intracellular cyclic adenosine monophosphate (cAMP) by inhibition of adenylyl cyclase. There is, however, also significant evidence that the apelin receptor may couple to Gαq, particularly in cardiomyocytes to activate phospholipase C (PLC) and protein kinase C (PKC).
In the heart, the apelin receptor may act as a mechanosensor for stretch in an apelin-independent/G protein-independent manner through recruitment of β-arrestin, a protein that initiates receptor internalization as well as downstream signaling.
In 2013 a second endogenous agonist for the apelin receptor, Elabela, was discovered. It was also independently given the name ‘Toddler’ after its identification as a mitogen during gastrulation. Elabela/Toddler is a 54 amino acid peptide, which is encoded by apela. Apela mutant zebrafish exhibit severe developmental defects, including rudimentary or absent heart formation. The studies predicted the existence of three mature Elabela/Toddler peptides with 32, 21 and 11 amino acids.
Role of Apelin/APJ in Physiology and Pathophysiology
Apelin and its receptor are implicated in various physiological processes, including the regulation of the cardiovascular system, fluid homeostasis and energy metabolism. There is also evidence that they play a role in conditions such as cardiac failure, cancer, and in metabolic disorders such as diabetes.
Apelin is a potent inotropic agent and vasodilator. Much of the interest in this peptide has focused on the potential therapeutic benefit of targeting the apelin receptor in pulmonary arterial hypertension (PAH) and heart failure (HF).
PAH is a fatal disease characterized by a progressive increase in pulmonary vascular resistance and pressure in the pulmonary circulation. It leads to right ventricular hypertrophy and eventually death from right ventricular failure.
There is evidence that the apelin/APJ axis appears to be important for maintaining pulmonary vascular homeostasis and therefore represents a potential target for PAH therapy. For example, serum apelin levels in PAH patients are significantly lower than those of controls. In mice, disruption of the apelin/APJ system exacerbates hypoxia-induced pulmonary hypertension. In monocrotaline-induced pulmonary hypertension apelin decreases myocardial injury and improves right ventricular function.
Enhancing apelin receptor signaling may also be beneficial in left ventricular HF. In humans, apelin plasma levels are decreased in late-stage HF. Apelin knockout mice develop progressive left ventricular dysfunction associated with aging and severe HF with pressure overload. In animal models of myocardial infarction (MI) and ischemia/reperfusion (I/R) injuries, apelin has been shown to have cardioprotective effects.
Apelin has been demonstrated to have roles in the uptake and retention of fluid. These responses appear mostly to be through interactions with regions of the central nervous system associated with arginine-vasopressin (AVP). In animal models, experimental data demonstrated that central injection of apelin into lactating rats inhibits the phasic electrical activity of AVP neurons, reduces plasma AVP levels, and increases aqueous diuresis. In the kidney, apelin increases diuresis by increasing renal blood flow and by counteracting the antidiuretic effect of AVP at the tubular level.
Apelin/APJ expression is elevated in a number of cancers indicating a potential role of this axis in the development and progression of cancers. Various studies suggest that apelin is involved in the proliferation and growth of tumors. Apelin increases the expression of factors involved in cell proliferation and activates signaling pathways that promote tumor growth and progression. It inhibits tumor cell apoptosis in several cancers and increases tumor stability. In addition, apelin has been identified as an angiogenic factor.
Apelin is also implicated in stimulating several metabolic functions such as glucose homeostasis. It inhibits insulin secretion and increases insulin sensitivity. Apelin is found to be increased in obese and type 2 diabetic individuals. The increased plasma apelin observed in type 2 diabetics has been proposed as a compensatory mechanism to directly counteract insulin resistance. In a recent trial, it was demonstrated that apelin administration improved insulin sensitivity in overweight men.
The apelin/APJ system is involved in various physiological and pathophysiological processes and therefore represents an attractive target for therapeutic interventions in cardiovascular diseases, cancer and metabolic disorders such as diabetes. Bachem offers a range of readily available apelin peptides and can also support your research with an excellent custom synthesis service.
|Product Number||Product Name|
|4038636||Apelin-12 (human, bovine, mouse, rat)|
|4029109||Apelin-13 (human, bovine, mouse, rat)|
|4104812||(Pyr¹)-Apelin-13 (human, bovine, mouse, rat) Acetate salt|
|4029110||(Pyr¹)-Apelin-13 (human, bovine, mouse, rat)|
|4050032||(Ala¹³)-Apelin-13 (human, bovine, mouse, rat) Trifluoroacetate salt|
|4095877||(Ala¹³)-Apelin-13 (human, bovine, mouse, rat) Acetate salt|
|4050029||Apelin-17 (human, bovine, mouse, rat) Trifluoroacetate salt|
|4086606||Apelin-36 (1-16) amide (human) Trifluoroacetate salt|
J.Masoumi, A.Jafarzadeh, H.Khorramdelazad, M.Abbasloui, J.Abdolalizadeh, N.Jamali, Role of Apelin/APJ axis in cancer development and progression. Advances in Medical Sciences 2020, 65, 202-213.
C.Read, D.Nyimanu, T.L.Williams, D.J.Huggins, P.Sulentic, R.G.C.Macrae et al, International Union of Basic and Clinical Pharmacology. CVII. Structure and pharmacology of the apelin receptor with a recommendation that Elabela/Toddler is a second endogenous peptide ligand. Pharmacological Reviews 2019, 71, 467-502.
P.Gourdy, L.Cazals, C.Thalamas, A.Sommet, F.Calvas, M.Galitzky et al, Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic-euglycaemic clamp. Diabetes, Obesity and Metabolism 2018, 20, 157-164.
M.B.Wysocka, K.Pietraszek-Gremplewicz, D.Nowak, The role of apelin in cardiovascular diseases, Obesity and Cancer. Frontiers in Physiology 2018, 9, 557.
C.Bertrand, P.Valet, I.Castan-Laurell, Apelin and energy metabolism. Frontiers in Physiology 2015, 6, 115.
P.Yang, J.J.Maguire, A.P.Davenport, Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends in Pharmacological Sciences 2015, 36, 560-567.
Apelin, a ligand of the orphan G protein-coupled receptor APJ, belongs to the family of adipokines. The distribution of apelin and APJ suggests that the apelin/APJ system is involved in a wide range of physiological and pathological processes. For example, the apelin/APJ system plays a role in the regulation of blood pressure, angiogenesis, and energy metabolism in addition to pathological processes such as heart failure, obesity, diabetes and cancer (1). Potential drugs targeting APJ and apelin have garnered interest in many of these areas. At present, there are apelin peptides in preclinical development as shown in Table 1.
|Product Name||Company or Organization||Highest Phase||Indication|
|CB5064 analogs||CohBar||Preclinical||Type 2 Diabetes|
|APJ receptor agonist||French National Institute of Health and Medical Research||Preclinical||Cognitive Disorders|
|Apelin-13 analogs||University of Ulster||Preclinical||Type 2 Diabetes, Obesity|
CohBar is developing CB5064 analogs for the treatment of type 2 diabetes and other metabolic diseases. CB5064 is a mitochondrially encoded peptide and an agonist of the apelin receptor (1). In June 2019, the company presented a poster on the preclinical data of CB5064 analogs at the American Diabetes Association Scientific Sessions. The studies demonstrated that peptide analogs of CB5064 show agonist activity at the apelin receptor and were effective in body weight reduction and improved glucose tolerance in diet-induced obese (DIO) mice (2).
An apelin peptide is under development by the French National Institute of Health and Medical Research for the treatment of postoperative cognitive dysfunction. Research has shown that this apelin receptor agonist reduced pain inflammation and postoperative cognitive impairment in a mouse model of closed tibial fracture (1).
The University of Ulster is developing fatty acid analogs of apelin-13 for the treatment of type 2 diabetes and obesity. These analogs act as apelin receptor agonists. In preclinical studies, one of the apelin-13 analogs induced a significant decrease in bodyweight compared to liraglutide (1). In addition, research has shown that the analogs have similar glucose lowering capabilities to GLP-1 but superior lipid lowering effects (3).
Synthetic apelin agonists have shown potential as therapeutics for type 2 diabetes, obesity and cognitive impairment. In addition, apelin peptides are of interest in the areas oncology and cardiovascular disease. For organizations and researchers studying the apelin/APJ system, Bachem offers apelin research peptides. In addition, Bachem offers a custom peptide synthesis service and the production of New Chemical Entities.
1. M.B.Wysocka, K.Pietraszek-Gremplewicz and D.Nowak. The role of apelin in cardiovascular diseases, obesity and cancer. Frontiers in Physiology 2018, 9, 557.
2. GlobalData 2020.
3. K.Grindstaff et al. Novel analogs of the mitochondrially encoded peptide CB5064 improve body weight and glucose tolerance in DIO mice. ADA 19th Scientific Sessions 2010.
4. O.Lynch, APJ receptor agonists provide for improved metabolic control and weight loss. Ulster University 2014.
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Interesting news about peptides in basic research and pharmaceutical development:
Potential treatment for chronic pain-ScienceDaily
New potential therapeutic candidate found for early type 2 diabetic retinopathy-Genetic Engineering & Biotechnology News