Apelin

Apelin is an endogenous peptide ligand of the G-protein-coupled receptor APJ (also known as AGTRL1 or APLNR), encoded by the APLN gene and existing in multiple active isoforms including apelin-36, -17, -13, and pyroglutamated apelin-13. PMID 38089606PMID 29875677PMID 21725702 Apelin is classified as an adipokine because it is produced and secreted by adipocytes, though it is also widely expressed in cardiovascular, nervous, renal, and other tissues. PMID 29875677PMID 21725702

of apelin are diverse and include regulation of cardiovascular physiology (positive inotropic effects, vasodilation, blood pressure control), angiogenesis, energy metabolism, fluid homeostasis, cell proliferation, and apoptosis. PMID 29875677PMID 33679444PMID 36611944 Apelin improves glucose and lipid metabolism, promotes mitochondrial oxidation and biogenesis, and mitigates oxidative stress and inflammatory pathways. PMID 40886173 In the cardiovascular system specifically, apelin enhances cardiac contractility, increases stroke volume, promotes diuresis, and exerts cardioprotective effects by reducing maladaptive hypertrophy, inflammation, and fibrosis. PMID 40886173PMID 36523134PMID 41155377

(exercise-sensitive factor) because its expression and secretion are regulated by various forms of exercise. PMID 38089606 The classification as an exerkine is supported by evidence that apelin responds to physical activity and may mediate some of the beneficial metabolic effects of exercise, particularly in the context of metabolic disease prevention and treatment. PMID 38089606 This exercise-responsive characteristic, combined with its role in energy metabolism and its secretion by adipose tissue, positions apelin as both an adipokine and an exerkine that links physical activity to metabolic health outcomes.

The apelinergic system shows promise for treating heart failure, pulmonary arterial hypertension, and coronary artery disease. PMID 34801627PMID 31236974PMID 27825851 Apelin exerts positive inotropic effects in both healthy and failing hearts, promotes vasodilation, and mitigates maladaptive cardiac hypertrophy, inflammation, and fibrosis. PMID 40886173PMID 27825851 In heart failure with reduced ejection fraction (HFrEF), serum apelin levels are decreased and have adverse prognostic significance. PMID 40886173 The peptide also demonstrates cardioprotective effects against ischemia/reperfusion injury and post-ischemic remodeling. PMID 30659278

Metabolic and Renal Disorders. Apelin demonstrates anti-diabetic and anti-obesity properties through improved glucose and lipid metabolism, enhanced mitochondrial oxidation, and promotion of brown adipogenesis. PMID 40886173PMID 26007641PMID 33838166 The system also shows therapeutic potential for insulin resistance, hyponatremia, and preeclampsia. PMID 34801627PMID 31236974 Apelin decreases epithelial sodium channel activity and inhibits vasopressin actions on renal collecting tubules, promoting diuresis. PMID 40886173

Hypertension. Systemic administration of apelin-13 or its modified form (pyroglutamate apelin-13) exerts vasodilatory and antihypertensive effects. PMID 27258138 The peptide antagonizes the renin-angiotensin system by promoting ACE2 transcription and antagonizing angiotensin II effects. PMID 32901821

Therapeutic Challenges. A major limitation is that native apelin peptides are rapidly degraded by endogenous peptidases including ACE2, neprilysin, and kallikrein. PMID 34801627PMID 32901821 This has driven development of metabolically stable apelin analogs and synthetic non-peptide APJ receptor agonists as more viable therapeutic alternatives. PMID 34801627PMID 31236974PMID 27825851