Apelin-13
APJ endogenous ligand, [Pyr1]apelin-13 (pyroglutamyl form), APLN gene product
Apelin-13 is a short fragment of the apelin precursor and the most potent endogenous agonist at the apelin receptor (APJ). It is a powerful positive inotrope and vasodilator, and unusually among cardiovascular peptides it opposes the renin-angiotensin system. Short human infusion studies show consistent haemodynamic effects, but no therapeutic programme has yet succeeded.
Mechanism
The APLN gene encodes a 77-residue preproprotein processed to apelin-36, apelin-17 and apelin-13, with potency running broadly in the reverse order of length. All act at APJ (gene APLNR), a class A GPCR sharing roughly 30 per cent homology with the angiotensin II type 1 receptor but not binding angiotensin II. APJ couples to Gi/Go, inhibiting adenylate cyclase, and recruits beta-arrestin with rapid internalisation, which underlies the marked tachyphylaxis seen on sustained exposure.
In the vasculature, endothelial APJ activation raises nitric oxide production through eNOS phosphorylation, causing vasodilatation; in vascular smooth muscle denuded of endothelium, apelin can instead constrict. In cardiomyocytes it increases contractility at subnanomolar concentrations through sodium-hydrogen exchange and sodium-calcium exchange, without raising intracellular cyclic AMP, so it augments contraction without the oxygen cost and arrhythmia risk of beta-adrenergic agonists. Angiotensin-converting enzyme 2 inactivates apelin, placing the peptide at a direct regulatory junction with the renin-angiotensin system.
What the research shows
The pivotal human work infused [Pyr1]apelin-13 systemically in patients with chronic heart failure and healthy controls, raising cardiac index and lowering mean arterial pressure and peripheral vascular resistance. Intracoronary apelin increased coronary blood flow and contractility indices while reducing left ventricular filling pressures. The direction and consistency of these findings across preparations is the strongest argument for APJ as a target.
Translation has nonetheless been difficult. Rapid degradation by ACE2 and neprilysin, and receptor desensitisation on sustained agonism, limit the native peptide to infusion. CLR325, a cyclic apelin-13 analogue, completed a phase 2 study in chronic stable heart failure but produced no results publication and did not progress. Small-molecule APJ agonists such as BMS-986224 have been characterised in vitro and in animals without a positive registration trial. There is at present no evidence that apelin agonism improves any clinical outcome in humans.
Evidence assessment
Mixed evidence
A genuine published randomised controlled human infusion study exists and shows consistent, reproducible haemodynamic effects, which is more than most peptides in this class can claim. But it is short, small and physiological rather than therapeutic. No outcome trial has been completed, and the one registered clinical analogue study did not lead to a results publication or further development.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor Preclinical only
Identified apelin as the endogenous ligand for the orphan receptor APJ, establishing the apelinergic system.
Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure Preclinical only
[Pyr1]apelin-13 raised cardiac index and lowered mean arterial pressure and peripheral vascular resistance; intracoronary apelin increased coronary flow and contractility indices. Acute physiological endpoints only, no clinical outcomes.
In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure Preclinical only
An orally viable small-molecule APJ agonist reproduced apelin haemodynamics in animals, showing the pathway is druggable without a peptide. No human data.
A study of CLR325 in chronic stable heart failure patients Preclinical only
A synthetic apelin-13 analogue was evaluated in chronic stable heart failure. No results publication exists and the programme did not advance.
Safety
Human exposure is limited to short supervised infusions in research settings, where the main effects were dose-related falls in blood pressure and reflex changes in heart rate. Beyond that, safety is essentially uncharacterised: there are no repeat-dose human data, no long-term toxicology in the public domain, and apelin signalling has roles in angiogenesis and tumour biology that would need careful evaluation.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation. Unlicensed peptide; supply for human consumption is not lawful under the Human Medicines Regulations 2012. |
| United States | No FDA-approved apelin product. Studied only under investigational applications. Material sold to consumers is an unapproved research chemical. |
| WADA (sport) | Not individually listed. Prohibited at all times under section S0 as a non-approved substance. Its effects on vascularisation could also invite scrutiny under the growth factor provisions of section S2. |
Questions
No. It produces favourable haemodynamic changes during short infusions in research settings, but no trial has shown it improves symptoms, hospitalisation or survival, and no regulator has approved any apelin product.
Cyclising the N-terminal glutamine to pyroglutamate blocks aminopeptidase attack, so the pyroglutamyl form is the dominant and most stable apelin isoform in human plasma. It is the physiologically relevant species, and it is a distinct chemical entity from unmodified apelin-13.