Apelin

Overview

Apelin is an endogenous peptide hormone identified in 1998 by Tatemoto and colleagues through screening for ligands of the orphan G protein-coupled receptor APJ (putative angiotensin receptor-like 1), which had been cloned in 1993 by O'Dowd and colleagues based on its ~30% sequence identity with the angiotensin II AT1 receptor. The discovery of apelin as APJ's endogenous ligand — followed in 2013 by the identification of a second APJ ligand, elabela — established the apelinergic system as a pharmacologically important axis with broad physiological roles.

Apelin is produced as a 77-amino acid preproprotein encoded by the APLN gene and processed to several bioactive C-terminal fragments of different lengths: apelin-36, apelin-17, and apelin-13, with a pyroglutamate-modified form of apelin-13 (Pyr¹-apelin-13) being the predominant circulating species in human plasma. These forms differ in their stability, receptor binding kinetics, and bioactivity, generating a peptide family of considerable pharmacological complexity.

The apelinergic system influences cardiovascular function (inotropic effects, vasodilation, and blood pressure modulation), fluid homeostasis (opposing vasopressin), angiogenesis (particularly in embryonic vessel development), adipose tissue function (apelin is a secreted adipokine), glucose metabolism, and feeding behavior. Its close relationship to the angiotensin system — sharing a paralogous GPCR and partially counterregulatory physiology — parallels the angiotensin-(1-7)/Mas system, making the apelin axis another "balancing" influence in cardiovascular biology.

Structure/Sequence

Forms of Apelin

Apelin-13: QRPRLSHKGPMPF-OH (residues 65-77 of preproprotein)

Pyr¹-Apelin-13: pyroglu-RPRLSHKGPMPF-OH (most abundant circulating form in plasma)

Apelin-17: KFRRQRPRLSHKGPMPF-OH (residues 61-77)

Apelin-36: LVQPRGSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF-OH (residues 42-77)

• Gene: APLN (X chromosome, Xq25-q26.1)
• Preproprotein: 77 amino acids with N-terminal signal peptide
• C-terminal RPRLSHKGPMPF: Core pharmacophore shared by all mature forms
• C-terminal phenylalanine: Critical for receptor binding and activation; removal by ACE2 inactivates
• Pyroglutamate modification: Confers stability to apelin-13

Species Conservation

The C-terminal 13 residues are highly conserved across mammals. Apelin-36 has greater species variability in the N-terminal extension.

Processing

Apelin-36 is further processed to shorter forms by unidentified proteases. Different tissues generate different apelin forms, contributing to tissue-specific signaling.

Mechanism of Action

APJ Receptor

All apelin forms signal through the APJ receptor (APLNR):

• Gi/o-coupled: Inhibits adenylyl cyclase → ↓cAMP
• PI3K/Akt activation
• MAPK/ERK activation
• β-arrestin recruitment: Apelin forms differ in relative G-protein vs β-arrestin signaling, generating biased agonism opportunities
• Receptor internalization: Apelin-13 causes more receptor endocytosis than apelin-17 in some assays

Cardiovascular Effects

• Positive inotropy: Most potent inotropic agent yet described per mass
• Vasodilation: NO-mediated in intact endothelium; vasoconstriction in absence of endothelium
• Blood pressure: Lowers BP through NO-dependent vasodilation
• Opposes angiotensin II: AT1R and APJ receptor heterodimerize, mutually antagonizing
• Cardioprotection in ischemia-reperfusion models

Fluid Balance

Apelin opposes vasopressin:

• Inhibits vasopressin release from supraoptic nucleus
• Promotes diuresis
• APJ and V1a receptors co-expressed in magnocellular neurons

Metabolic Effects

• Improves insulin sensitivity
• Stimulates glucose uptake in skeletal muscle
• Reduces hepatic glucose output
• Modulates adipocyte function (apelin is an adipokine)
• Affects appetite — central effects on feeding behavior

Vascular Development

• Critical for embryonic vascular development
• APJ-/- mice have cardiovascular defects
• Angiogenic effects in ischemic tissue
• Role in retinal vascularization

ACE2-Mediated Inactivation

Apelin-13 is a physiological substrate of ACE2, which removes its C-terminal phenylalanine to produce apelin-13(1-12) — an inactive metabolite. This places apelin in the ACE2 proteolytic network alongside angiotensin II/Ang-(1-7).

Research Summary

Common Discussion Topics

1. APJ/AT1 paralogy and counterregulation — The APJ and AT1 receptors are close paralogs. Apelin opposes many angiotensin II effects on vasoreactivity and fluid balance, creating a receptor-level counterregulatory system distinct from but parallel to the angiotensin-(1-7)/Mas axis.

2. Multiple mature forms — Apelin-13, apelin-17, apelin-36, and Pyr¹-apelin-13 are all bioactive but have different pharmacokinetics and signaling profiles. This complexity has required careful definition of which species are being studied in any given experiment.

3. Elabela as second ligand — The identification of elabela (also called apela or toddler) as a second APJ ligand demonstrated that orphan and deorphanized receptors may have multiple endogenous peptide ligands, as had been shown for angiotensin-(1-7)/Mas and other systems.

4. Inotropic potency — Apelin is the most potent positive inotropic agent known per mass. This has driven interest in apelin analogs for heart failure research, though clinical translation has been complicated by short half-life and the need for continuous administration.

5. ACE2 linkage to coronavirus biology — Because ACE2 cleaves both angiotensin II and apelin-13, the COVID-19 pandemic — in which ACE2 is the viral receptor — brought renewed attention to the apelinergic system as potentially dysregulated in severe infection.

Related Compounds

• Elabela — second APJ receptor endogenous ligand
• Angiotensin II — related peptide acting at paralogous receptor
• Angiotensin-(1-7) — counterregulatory RAS peptide
• Leptin — adipokine with overlapping metabolic biology