Apelin

Apelin is a family of bioactive peptides discovered in 1998 by Tatemoto and colleagues as the endogenous ligand of the APJ receptor (now called the apelin receptor), a G-protein coupled receptor that had been an orphan receptor since its discovery in 1993. Apelin peptides are derived from a 77-amino acid preproapelin precursor, yielding several active forms including apelin-36, apelin-17, apelin-13, and pyroglutamated [Pyr1]apelin-13, the last of which is the most potent and predominant form in the cardiovascular system.

Apelin and its receptor are widely expressed in the cardiovascular system, including the heart, vascular endothelium, and smooth muscle. In the heart, apelin acts as a potent positive inotrope — it increases cardiac contractility without increasing heart rate or causing the energy-inefficient calcium overload associated with traditional inotropes like dobutamine. This makes the apelin system an attractive therapeutic target for heart failure, where impaired contractility is a central problem.

In the vasculature, apelin causes nitric oxide-dependent vasodilation, reducing peripheral resistance and blood pressure. It also has important roles in fluid homeostasis as a counter-regulatory peptide to the vasopressin system — apelin inhibits vasopressin release and promotes aquaresis (water excretion without significant electrolyte loss). In heart failure patients, circulating apelin levels are reduced, and the degree of reduction correlates with disease severity.

Preclinical and early clinical research has explored apelin and its analogs for heart failure treatment. Studies have shown that apelin infusion improves cardiac output and reduces vascular resistance in heart failure patients. The development of longer-acting apelin analogs and small-molecule apelin receptor agonists is an active area of pharmaceutical research, with several compounds in preclinical and early clinical development.