Apelin
Apelin is the endogenous peptide ligand of the APJ receptor (APLNR), existing in multiple bioactive isoforms including apelin-36, apelin-17, apelin-13, and [Pyr1]apelin-13. Apelin is a positive inotrope and vasodilator that increases cardiac output without increasing afterload, with significant research applications in pulmonary arterial hypertension, heart failure, and fluid homeostasis.
Apelin is a family of endogenous peptide ligands for the APJ receptor (now designated APLNR, apelin receptor), a G protein-coupled receptor originally identified as an orphan receptor with sequence homology to the angiotensin II AT1 receptor. The apelin peptides were discovered in 1998 by Tatemoto et al. from bovine stomach extracts.
Overview
The apelin/APLNR system is expressed widely throughout the cardiovascular system, with particularly high levels in the heart (cardiomyocytes and endocardium), lung vasculature, kidney, central nervous system, and adipose tissue. APLNR is a class A (rhodopsin-like) GPCR that couples to Gi/o proteins, leading to inhibition of adenylyl cyclase and activation of downstream signaling through ERK1/2, PI3K/Akt, and phospholipase C pathways.
Apelin has several distinguishing features as a cardiovascular peptide. First, it acts as a positive inotrope without the arrhythmogenic risks associated with beta-adrenergic agonists or phosphodiesterase inhibitors, making it an attractive candidate for heart failure treatment. Second, its combined inotropic and vasodilatory effects produce a hemodynamic profile characterized by increased cardiac output with decreased systemic and pulmonary vascular resistance — an ideal hemodynamic signature for heart failure. Third, apelin counteracts the vasopressin system by inhibiting vasopressin release from the hypothalamus and opposing vasopressin's antidiuretic effects in the collecting duct, playing a role in fluid homeostasis.
Elabela (ELA, also called Toddler or Apela) was identified in 2013 as a second endogenous ligand for APLNR, adding complexity to the apelin system. ELA is essential for cardiovascular development and may have distinct signaling properties from apelin at the same receptor.
Mechanism of Action
Apelin activates APLNR through multiple signaling cascades with distinct cardiovascular effects:
Positive Inotropy via PLCbeta/IP3/Ca2+ and Na+/H+ Exchange: Apelin increases cardiac contractility through two primary mechanisms. First, PLCbeta activation generates IP3, which releases calcium from sarcoplasmic reticulum stores. Second, apelin activates the Na+/H+ exchanger (NHE), increasing intracellular sodium, which drives the Na+/Ca2+ exchanger (NCX) in reverse mode, increasing cytosolic calcium. This combination produces a sustained increase in calcium transients and contractile force without increasing cAMP — distinguishing it mechanistically from beta-adrenergic stimulation and reducing arrhythmogenic potential.
Vasodilation via eNOS/NO Pathway: In endothelial cells, apelin activates APLNR-mediated PI3K/Akt signaling, which phosphorylates and activates eNOS at Ser1177, increasing nitric oxide production. NO diffuses to adjacent vascular smooth muscle, activating soluble guanylyl cyclase and producing cGMP-mediated vasodilation. This endothelium-dependent vasodilation reduces both systemic and pulmonary vascular resistance.
Counter-regulation of Vasopressin: Apelin is co-localized with vasopressin in magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei. Apelin inhibits vasopressin release and opposes vasopressin's antidiuretic action in the collecting duct, promoting aquaresis (free water excretion without natriuresis). This makes the apelin system a functional antagonist of the vasopressin pathway, relevant to fluid homeostasis in heart failure.
Anti-hypertrophic and Anti-fibrotic Effects: Apelin/APLNR signaling activates AMPK and inhibits the angiotensin II-mediated calcineurin/NFAT hypertrophic pathway in cardiomyocytes. Apelin also reduces cardiac fibrosis by inhibiting TGF-beta/Smad signaling in cardiac fibroblasts and by reducing endothelin-1 expression. These effects protect against pathological cardiac remodeling.
Angiogenesis: Apelin is a potent angiogenic factor that promotes endothelial cell proliferation, migration, and tube formation through APLNR/PI3K/Akt and ERK1/2 signaling. Apelin expression is upregulated by hypoxia through HIF-1alpha, making it a key mediator of ischemia-driven neovascularization.
Metabolic Effects: Apelin increases glucose uptake in skeletal muscle and adipose tissue through AMPK-mediated GLUT4 translocation, improves insulin sensitivity, and stimulates energy expenditure. These metabolic actions have prompted research into apelin for obesity and type 2 diabetes.
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Research
Apelin and Fluid Homeostasis
The apelin/vasopressin counter-regulatory system plays an important role in fluid balance. Apelin promotes aquaresis (excretion of free water without sodium) by opposing vasopressin's V2 receptor-mediated actions in the collecting duct. In animal models of heart failure, apelin levels are decreased while vasopressin is increased, contributing to water retention and hyponatremia. De Mota et al. demonstrated that intracerebroventricular apelin injection inhibits the phasic firing of vasopressin neurons and reduces plasma vasopressin levels. De Mota et al. (2004) — Proc. Natl. Acad. Sci. USA This vasopressin-antagonistic effect makes apelin an endogenous "aquaretic" and a potential therapeutic target for hyponatremia and fluid overload in heart failure.
Apelin in Diabetes and Metabolism
Apelin is an adipokine secreted by adipose tissue, and its levels are altered in obesity and type 2 diabetes. Apelin improves insulin sensitivity through AMPK activation and increases glucose uptake in skeletal muscle and adipose tissue. In ob/ob mice and high-fat diet-induced obese mice, chronic apelin administration improved glucose homeostasis and reduced adiposity. Dray et al. (2008) — Cell Metab. However, in human studies, apelin levels are paradoxically elevated in obesity and type 2 diabetes, possibly as a compensatory response or reflecting apelin resistance analogous to insulin resistance. The role of apelin in human metabolic disease remains an active area of investigation.
Synthetic Apelin Receptor Agonists
Due to the short plasma half-life of native apelin peptides (~5-8 minutes), several groups have developed metabolically stable APLNR agonists for therapeutic use. MM07 is a cyclic apelin analog with improved stability that has been tested in healthy volunteers and PAH patients, showing hemodynamic improvements. Yang et al. (2017) — J. Am. Heart Assoc. CMF-019 (BMS-986224) is a small molecule APLNR agonist developed by Bristol-Myers Squibb that has shown efficacy in preclinical heart failure and PAH models. BGE-105 (Bayer) and other APLNR agonists are in various stages of preclinical and clinical development. The challenge for apelin therapeutics is achieving sustained receptor activation without desensitization.
Apelin in Heart Failure
Apelin levels are significantly reduced in chronic heart failure, and the degree of reduction correlates with disease severity. This reduction may contribute to the hemodynamic deterioration of heart failure by removing the positive inotropic and vasodilatory support provided by endogenous apelin. Japp et al. conducted a landmark study demonstrating that apelin infusion in patients with chronic heart failure produced significant increases in cardiac output and cardiac index, with simultaneous reductions in systemic vascular resistance and mean arterial pressure, without causing tachycardia or arrhythmias. Japp et al. (2010) — Circulation This hemodynamic profile — increased inotropy with decreased afterload and no proarrhythmic effect — distinguishes apelin from conventional inotropes (dobutamine, milrinone) and makes it a potentially transformative therapy for acute and chronic heart failure. Chong et al. confirmed these findings and demonstrated that apelin increases coronary blood flow and improves myocardial energetics in heart failure patients. Chong et al. (2006) — Heart
Apelin in Pulmonary Arterial Hypertension
The apelin/APLNR system plays a critical role in pulmonary vascular biology. APLNR is highly expressed on pulmonary endothelial cells, and apelin signaling promotes endothelial survival, maintains pulmonary vascular homeostasis, and opposes the pulmonary vascular remodeling that characterizes PAH. In PAH patients, circulating apelin levels are significantly reduced, and lung tissue from PAH patients shows decreased apelin and APLNR expression. Kim et al. (2013) — Arterioscler. Thromb. Vasc. Biol. Animal models have demonstrated that apelin knockout mice develop more severe pulmonary hypertension in response to hypoxia or monocrotaline, while exogenous apelin administration attenuates pulmonary vascular remodeling and reduces pulmonary artery pressure. These findings have spurred development of apelin receptor agonists for PAH therapy.
Safety Profile
Apelin peptides have been administered intravenously to healthy volunteers and patients with heart failure and pulmonary hypertension in Phase 1/2 studies without serious adverse events. The most notable hemodynamic effects — reduced blood pressure and increased heart rate — are pharmacologically predictable and dose-dependent. At therapeutic doses producing hemodynamic benefit, systolic blood pressure typically decreases by 5-15 mmHg, which is generally well-tolerated. Unlike beta-adrenergic agonists and phosphodiesterase inhibitors, apelin has not been associated with proarrhythmic effects in human studies, which is a significant potential safety advantage for heart failure therapy. The short half-life of native apelin peptides (5-8 minutes) means that adverse effects are rapidly reversible upon discontinuation of infusion. Longer-acting analogs (MM07) have also shown acceptable safety profiles in early clinical studies. No immunogenicity, hepatotoxicity, or nephrotoxicity has been reported. Theoretical concerns include the angiogenic effects of apelin, which could potentially promote tumor neovascularization, though this has not been observed clinically.
Clinical Research Protocols
- Apelin infusion (investigational — HF): [Pyr1]apelin-13 or apelin-36 infusion at 10-300 nmol/min IV for 4-6 minutes (bolus studies) or 30-120 minutes (hemodynamic studies). Japp et al. used incremental doses of apelin infusion with invasive hemodynamic monitoring.
- MM07 (cyclic apelin analog): Studied at doses up to 135 nmol/min IV infusion in healthy volunteers and PAH patients, with hemodynamic monitoring.
- Apelin biomarker measurement: Plasma apelin measured by radioimmunoassay or ELISA. Reference ranges: approximately 200-500 pg/mL in healthy subjects (assay-dependent). Reduced levels (<200 pg/mL) associated with heart failure severity.
- Key trials: Japp et al. 2010 (apelin in HF), Brash et al. 2018 (apelin in PAH), Yang et al. 2017 (Elabela in PAH), MM07 studies.
- Hemodynamic monitoring: Right heart catheterization recommended during investigational apelin infusion to measure cardiac output, pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance.
Subpopulation Research
- Chronic heart failure (HFrEF): Apelin levels are reduced and correlate with disease severity (NYHA class, LVEF). Infusion studies show beneficial hemodynamic effects — increased cardiac output, decreased SVR, no arrhythmias (PMID: 20208978).
- Pulmonary arterial hypertension: Apelin and APLNR expression are decreased in lung tissue. Apelin infusion reduces PVR and increases cardiac output. APLNR agonists are in development for PAH (PMID: 23950141).
- Type 2 diabetes and obesity: Apelin levels are paradoxically elevated but may reflect apelin resistance. Exogenous apelin improves glucose homeostasis in animal models (PMID: 18996000).
- Preeclampsia: Circulating apelin and Elabela levels are reduced in preeclampsia, and APLNR signaling is important for placental vascular development.
- Chronic kidney disease: Apelin levels are elevated in CKD, possibly as a compensatory response to fluid overload. The aquaretic properties of apelin may be relevant to fluid management.
- Congenital heart disease: APLNR mutations have been identified in congenital heart defects, supporting the developmental role of the apelin/Elabela system (Elabela knockout is embryonically lethal in zebrafish).
- Aging: Apelin levels decline with aging, and age-related reduction in apelin signaling may contribute to sarcopenia, cardiac aging, and vascular stiffness.
Pharmacokinetic Profile
Apelin — Pharmacokinetic Curve
Intravenous infusion (investigational)Ongoing & Future Research
- APLNR agonists for PAH and HF: Multiple pharmaceutical programs are developing metabolically stable small molecule and peptide APLNR agonists for clinical use in pulmonary hypertension and heart failure.
- Biased APLNR agonists: Development of agonists that selectively activate G protein signaling without beta-arrestin recruitment, potentially providing sustained receptor activation without desensitization.
- Apelin in cardiac regeneration: Apelin promotes cardiomyocyte proliferation in neonatal hearts and may enhance endogenous cardiac repair mechanisms after myocardial infarction.
- Elabela/Toddler biology: Investigation of Elabela as a second APLNR ligand with potentially distinct signaling properties and therapeutic applications, particularly in cardiovascular development and vascular homeostasis.
- Apelin for hyponatremia: Clinical development of apelin or APLNR agonists as aquaretic agents for heart failure-associated hyponatremia, as an alternative or adjunct to vaptans.
- Apelin in exercise physiology: Apelin is released during exercise and mediates some of the cardiovascular and metabolic benefits of physical activity. Exercise-induced apelin release may explain part of the cardioprotective effect of exercise training.
Quick Start
- Route
- Intravenous infusion (investigational)
Molecular Structure
- Formula
- C62H98N18O13S (apelin-13)
- Weight
- 253.19 Da
- CAS
- 217082-60-5 (apelin-13)
- PubChem CID
- 44560306
- Exact Mass
- 253.0715 Da
- LogP
- -4.2
- TPSA
- 138 Ų
- H-Bond Donors
- 4
- H-Bond Acceptors
- 7
- Rotatable Bonds
- 7
- Complexity
- 318
Identifiers (SMILES, InChI)
InChI=1S/C8H16NO6P/c1-5(8(12)13)4-16(14,15)6(9)2-3-7(10)11/h5-6H,2-4,9H2,1H3,(H,10,11)(H,12,13)(H,14,15)
BHEFSCJVACOHGZ-UHFFFAOYSA-NResearch Indications
Cardiovascular
Preclinical and early clinical evidence shows apelin/APJ activation improves cardiac contractility (positive inotropy), promotes vasodilation, and reduces afterload. PEGylated apelin-36 increased ejection fraction in MI rat models without altering blood pressure.
Apelin system opposes vasoconstriction in pulmonary vasculature. Reduced apelin levels correlate with PAH severity. APJ agonists under investigation as potential vasodilatory therapy for PAH.
Systemic apelin administration reduces systolic and diastolic blood pressure via endothelium-dependent vasodilation. Opposes the renin-angiotensin and vasopressin systems. Short half-life limits current clinical application.
Metabolic
Clinical studies show altered apelin levels in diabetic patients. Apelin improves glucose homeostasis and insulin sensitivity in preclinical models. Serum apelin is significantly elevated in T1D patients and correlates with vascular changes.
Apelin regulates energy metabolism and adipose tissue function. Preclinical evidence supports role in improving metabolic flexibility and reducing inflammation in obesity models.
Research Protocols
intravenous Injection
Safety Profile Apelin peptides have been administered intravenously to healthy volunteers and patients with heart failure and pulmonary hypertension in Phase 1/2 studies without serious adverse events.
intracerebroventricular Injection
demonstrated that intracerebroventricular apelin injection inhibits the phasic firing of vasopressin neurons and reduces plasma vasopressin levels.
What to Expect
What to Expect
Rapid onset expected; half-life of ~5-8 minutes (plasma) indicates fast-acting pharmacokinetics
Apelin infusion (investigational — HF): [Pyr1]apelin-13 or apelin-36 infusion at 10-300 nmol/min IV for 4-6 minutes (bolus studies) or 30-120 minutes...
Due to short half-life (~5-8 minutes (plasma)), effects are expected per-dose; consistent daily administration maintains therapeutic levels
Regular administration schedule required; effects are dose-dependent and do not persist between doses
Quality Indicators
What to look for
- Well-established safety profile
- Multiple peer-reviewed studies available
Caution
- Short half-life may require frequent dosing
Red flags
- Significant side effect risk noted
- Liver toxicity concerns reported
Frequently Asked Questions
References (9)
- [4]De Mota, N. et al Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release Proc. Natl. Acad. Sci. USA (2004)
- [9]Brash, L. et al — Short-term hemodynamic effects of apelin in patients with pulmonary arterial hypertension JACC Basic Transl. Sci. (2018)
- [1]Tatemoto, K. et al Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor Biochem. Biophys. Res. Commun. (1998)
- [2]Japp, A. G. et al Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure Circulation (2010)
- [3]Kim, J. et al An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension Nat. Med. (2013)
- [5]Dray, C. et al Apelin stimulates glucose utilization in normal and obese insulin-resistant mice Cell Metab. (2008)
- [6]Read, C. et al International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor Pharmacol. Rev. (2019)
- [7]
- [8]Murza, A. et al — Discovery and Structure-Activity Relationship of Potent and Selective Apelin Receptor Agonists for Pulmonary Arterial Hypertension J. Med. Chem. (2022)
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