The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders

Abstract

The apelinergic pathway has been generating increasing interest in the past few years for its potential as a therapeutic target in several conditions associated with the cardiovascular and metabolic systems. Indeed, preclinical and, more recently, clinical evidence both point to this G protein-coupled receptor as a target of interest in the treatment of not only cardiovascular disorders such as heart failure, pulmonary arterial hypertension, atherosclerosis, or septic shock, but also of additional conditions such as water retention/hyponatremic disorders, type 2 diabetes, and preeclampsia. While it is a peculiar system with its two classes of endogenous ligand, the apelins and Elabela, its intricacies are a matter of continuing investigation to finely pinpoint its potential and how it enables crosstalk between the vasculature and organ systems of interest. In this perspective article, we first review the current knowledge on the role of the apelinergic pathway in the above systems, as well as the associated therapeutic indications and existing pharmacological tools. We also offer a perspective on the challenges and potential ahead to advance the apelinergic system as a target for therapeutic intervention in several key areas.

Keywords: Apela/Toddler/Elabela; apelin; apelin receptor/APLNR/APJ; cardiovascular protection; heart failure; hypertension; preeclampsia; pulmonary arterial hypertension; septic shock; type 2 diabetes; water retention/hyponatremic disorders.

Figure 1.

The different forms of apelin. Proteolysis of preproapelin at putative cleavage sites leads to three fragments of 36, 17, and 13 amino acids named apelin-36, apelin-17, and apelin-13, respectively. Pyroglutamylated apelin-13 is formed by spontaneous cyclization of apelin-13. The cleavage sites for neprilysin and angiotensin-converting enzyme 2 on apelin-13 and apelin-17 are indicated by red and purple double-headed arrows, respectively. The straight and dashed black arrows represent full and biased agonism of the different apelin forms, respectively.

Figure 2.

Schematic of the different apelinergic signaling pathways. The activation of apelin receptor by its endogenous ligands, apelin or Elabela, triggers various signaling pathways that exert protective cardiovascular and metabolic effects in the organism. Some of the transcriptional gene regulation effects following the activation of apelinergic pathway are depicted in the nucleus. Abbreviations: AC, adenylate cyclase; ACE2, angiotensin-converting enzyme 2; Ang II, angiotensin II; APLNR, apelin receptor; AT1R, angiotensin type 1 receptor; βARR, β-arrestins; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular-regulated kinases 1/2; FABP4, fatty acid binding protein 4; FOXO1/3, forkhead box protein O1/3; KDR, kinase insert domain receptor (also known as VEGFR2); MLCK, myosin light chain kinase; NEP, neprilysin; SIRT3, sirtuin 3; VEGFA, vascular endothelial growth factor A.

Figure 3.

The apelinergic system counteracts cardiovascular and metabolic failures. The activation of the apelinergic pathway results in multiple physiological effects that can alleviate an array of cardiovascular and metabolic disorders. Abbreviations: AVP, vasopressin; ECs, endothelial cells; MAP, mean arterial pressure; NO, nitric oxide; PAH, pulmonary arterial hypertension.

Figure 4.

Vasopressin and apelins—the yin and yang of water balance. The interrelated actions of apelins and vasopressin (AVP) are required to ensure and finely tune water balance in the entire organism. The hydration state determines the overall release of apelins and AVP from the hypothalamic magnocellular neurons into the bloodstream. Their opposing receptor-mediated functions in the brain and kidney results in the regulation of urine osmolality and volume.