Update on apelin peptides as putative targets for cardiovascular drug discovery

The physiological importance of GPCR/ligand pathways is highlighted by the fact that numerous pathologies are attributed to their signaling dysfunction. Over 50% of the pharmaceutical drugs currently used to treat human disease are based on compounds that interact with GPCRs. Apelin/APJ constitutes a novel endogenous peptide/GPCR system proposed to be involved in a wide range of physiological functions. Early evidence suggests that apelin/APJ may hold promise as a target for development of novel therapeutic agents which may counteract a number of pathologies including cardiovascular disease. Despite advances in treatment of cardiovascular disease, incidence, prevalence, morbidity and economic costs remain high necessitating the development of new treatment paradigms.

This review summarizes apelin/APJ structure, distribution and regulation; presents evidence for a role of apelin in pressure/volume homeostasis and in the pathophysiology of cardiovascular disease; summarizes data on beneficial effects of apelin in preclinical, animal models of cardiovascular disease and measurement of plasma levels of apelin across the full spectrum of cardiovascular disease in humans; and notes the first studies describing bioactivity of apelin peptides in human healthy volunteers and patients with heart failure.

More clarity is needed on the precise physiological/pathophysiological role of the apelin/APJ system in human health and disease. Nonetheless, preclinical studies and initial studies in humans show that APJ antagonism may represent a novel therapeutic target for patients with cardiovascular disease. Development of appropriately validated assays for apelin will clarify circulating levels of the peptide in health and disease. Development of suitable agonists/antagonists will pave the way for much needed future studies essential for advancing this promising field of drug discovery.