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phase 1Cardiovascular

Apelin

Also known as: Apelin-13, Apelin-36, Apelin-17, APLN, APJ Ligand

Apelin is a family of endogenous peptides (apelin-13, apelin-17, and apelin-36) that serve as ligands for the APJ receptor (now called the apelin receptor, APLNR). Discovered in 1998, apelin is expressed in the heart, vasculature, brain, adipose tissue, and kidneys. It functions as a potent cardiac inotrope, vasodilator, and diuretic. Apelin signaling is emerging as a critical pathway in heart failure, pulmonary arterial hypertension, and metabolic disease, with several apelin analogs entering early clinical trials.

4 cited references·6 researched benefits

Quick Answer

Apelin is an endogenous peptide family (apelin-13, -17, -36) that activates the APJ/apelin receptor in the heart and blood vessels. It increases cardiac contractility without raising oxygen demand, dilates blood vessels, promotes diuresis, and regulates fluid balance. Phase 1 clinical trials are exploring synthetic apelin analogs for heart failure and pulmonary arterial hypertension treatment.

Key Facts

Mechanism
Apelin peptides bind the apelin receptor (APLNR/APJ), a Gαi/q-coupled GPCR. In cardiomyocytes, apelin activates phospholipase C, increasing intracellular calcium via IP3 and activating protein kinase C, leading to enhanced cardiac contractility (positive inotropy) without increasing myocyte oxygen consumption. In vascular smooth muscle, apelin stimulates nitric oxide (NO) production via endothelial nitric oxide synthase (eNOS), causing vasodilation. Apelin also activates the PI3K/Akt survival pathway, providing anti-apoptotic protection to cardiomyocytes, and suppresses angiotensin II signaling through receptor heterodimerization of APJ with AT1 receptors. Apelin-13 (pyroglutamated form) is the most potent isoform.
Research Status
phase 1
Half-Life
~5-8 minutes (apelin-13); ~20 minutes (apelin-36)
Molecular Formula
C₆₃H₉₈N₁₈O₁₇S
Primary Use
Cardiovascular
Table of Contents

Benefits

  • Positive cardiac inotropy — increases contractile force without raising myocardial oxygen consumptionstrong
  • Vasodilation — reduces afterload through nitric oxide-dependent mechanismsstrong
  • Cardioprotection — reduces infarct size and apoptosis via PI3K/Akt signalingmoderate
  • Diuretic and aquaretic effects — promotes water excretion by opposing vasopressinmoderate
  • Pulmonary vasodilation — reduces pulmonary vascular resistance in PAH modelsmoderate
  • Metabolic benefits — enhances insulin sensitivity and glucose uptake in skeletal musclepreliminary

Dosage Protocols

RouteDosage RangeFrequencyNotes
Intravenous infusion (investigational)10-300 nmol/min (pyroglutamyl apelin-13)Continuous infusion in clinical studiesShort half-life requires continuous infusion. Dose-response studies in healthy volunteers and heart failure patients have established safety.
Subcutaneous injection (analog — investigational)Not establishedUnder developmentProtease-resistant apelin analogs (e.g., MM07, CMF-019, BMS-986224) are in preclinical/early clinical development to overcome short half-life.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Hypotension from vasodilationcommon
  • Tachycardia (reflexive, from blood pressure reduction)common
  • Flushing and warmthcommon
  • Headachecommon
  • Excessive fluid loss from diuretic/aquaretic effectsrare

Frequently Asked Questions

Why is apelin important in heart failure?
Apelin levels are significantly reduced in patients with chronic heart failure, and this deficiency correlates with disease severity. Unlike catecholamines (dobutamine), apelin increases cardiac contractility without raising myocardial oxygen demand — a highly desirable property in failing hearts that are already energy-starved. In clinical studies, intravenous apelin infusion improved cardiac output and reduced peripheral resistance in heart failure patients. Restoring apelin signaling is therefore a promising therapeutic strategy for heart failure, and several synthetic apelin receptor agonists are in development.
What is the apelin receptor (APJ)?
The apelin receptor (APJ, also known as APLNR) is a G-protein-coupled receptor first identified as an orphan receptor in 1993, five years before its endogenous ligand apelin was discovered. APJ is expressed in cardiomyocytes, vascular endothelium and smooth muscle, brain, kidney, and adipose tissue. Interestingly, APJ can also form heterodimers with the angiotensin AT1 receptor, and this interaction inhibits angiotensin II signaling. A second endogenous ligand for APJ, called ELABELA/Toddler, was discovered in 2013 and plays a critical role in embryonic cardiovascular development.
How does apelin interact with the renin-angiotensin system?
Apelin and angiotensin II have a fascinating counter-regulatory relationship. The apelin receptor (APJ) forms heterodimers with the angiotensin AT1 receptor, and apelin binding to APJ inhibits AT1 signaling. Additionally, ACE2 — the same enzyme that converts angiotensin II to the protective angiotensin-(1-7) — also processes apelin-13 into apelin-12, modulating its activity. Angiotensin II downregulates apelin expression, while apelin suppresses angiotensin II release. This reciprocal antagonism means the apelin system acts as an endogenous brake on the harmful effects of RAAS overactivation in cardiovascular disease.
Can apelin help with pulmonary hypertension?
Preclinical evidence strongly supports apelin as a target in pulmonary arterial hypertension (PAH). Apelin knockout mice develop pulmonary hypertension spontaneously, and PAH patients have markedly reduced circulating apelin levels. Apelin infusion reduces pulmonary vascular resistance and right ventricular afterload in animal models. The synthetic apelin analog MM07 demonstrated improved cardiac output and reduced pulmonary vascular resistance in a phase 1 study of PAH patients. Several pharmaceutical companies are developing long-acting apelin receptor agonists specifically for PAH.

References

  1. 1
    Isolation and characterization of apelin, the ligand of the APJ receptor(1998)PubMed ↗
  2. 2
    Apelin and the cardiovascular system: therapeutic potential and clinical evidence(2014)PubMed ↗
  3. 3
    Apelin increases cardiac contractility via protein kinase C-dependent mechanisms(2007)PubMed ↗
  4. 4
    The apelin-APJ axis in cardiovascular disease: emerging therapeutic strategies(2018)PubMed ↗

Latest Research

Last updated: 2026-02-19