Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system

Abstract

Apelin and its G protein-coupled receptor (GPCR) have emerged as a key signalling pathway in the cardiovascular system. The peptide is a potent inotropic agent and vasodilator. Remarkably, a peptide, Elabela/Toddler, that has little sequence similarity to apelin, has been proposed as a second endogenous apelin receptor ligand and is encoded by a gene from a region of the genome previously classified as 'non-coding'. Apelin is downregulated in pulmonary arterial hypertension and heart failure. To replace the missing endogenous peptide, 'biased' apelin agonists have been designed that preferentially activate G protein pathways, resulting in reduced β-arrestin recruitment and receptor internalisation, with the additional benefit of attenuating detrimental β-arrestin signalling. Proof-of-concept studies support the clinical potential for apelin receptor biased agonists.

Keywords: APJ; Elabela/Toddler; apelin; apelin receptor; biased agonist; pulmonary arterial hypertension.

Figure 1

Sequences of apelin and Elabela/Toddler peptides, apelin-36, [Pyr¹]apelin-13, Elabela/Toddler-32; Elabela/Toddler-21, Elabela/Toddler-11. Three-letter codes of amino acid residues are shown. pGlu, pyroglutamate; yellow lines represent disulfide bridges.

Figure 2

Proposed mechanisms of vasodilator and vasoconstrictor effects of apelin. (A) Apelin activates endothelial apelin receptors producing vasodilatation by pathways including release of NO. (B) In the absence of endothelium, apelin activates apelin receptors on the underlying smooth muscle to cause vasoconstriction. The apelin receptor is represented by the cell surface seven-transmembrane receptor in red; broken arrows indicate unspecified intermediate steps; + and − signs indicate positive and negative regulation, respectively. Abbreviations: BK_Ca, large-conductance Ca²⁺-activated K⁺ channel; eNOS, endothelial nitric oxide synthase; MLC, myosin light chain; MLC^P, phosphorylated myosin light chain; NCX, Na⁺/Ca²⁺ exchanger; NHE, Na⁺/H⁺ exchanger; NO, nitric oxide; PGI₂, prostacyclin; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; sGC, soluble guanylyl cyclase; VEC, vascular endothelial cells; VSMC, vascular smooth cells.

Figure 3

Proposed mechanisms of apelin-induced positive inotropy and apelin-independent stretch-induced hypertrophy. (A) Apelin activates apelin receptors on cardiomyocytes to induce positive inotropy. (B) The apelin receptor mediates β-arrestin-dependent signalling (orange) to cause hypertrophy in response to stretch, whereas apelin-activated G_αi signalling (black) is protective. The apelin receptor is represented by the cell surface seven-transmembrane receptor in red; broken arrows indicate unspecified intermediate steps; broken arrow with? mark indicates unknown intermediate steps; + and − signs indicate positive and negative regulation, respectively. Abbreviations: β-arr, β-arrestin; ERK1/2, extracellular signal-regulated kinase 1/2; IP₃, inositol trisphosphate; MEK1/2, mitogen-activated protein kinase kinases 1/2; MLC, myosin light chain; MLCK, myosin light chain kinase; NCX, Na⁺/Ca²⁺ exchanger; NHE1, Na⁺/H⁺ exchanger 1; PKCɛ, protein kinase Cɛ; PLC, phospholipase C; SR, sarcoplasmic reticulum.

Figure 4

Summary of reported causes and consequences of reduced vascular apelin levels in pulmonary arterial hypertension (PAH) lung. In PAH, reduced BMPR-II expression and function, together with other stimuli, cause a reduction in endothelial PPARγ and, as a consequence, a reduction in the expression of the PPARγ transcriptional target apelin. Loss of apelin results in disinhibition of FGF2-stimulated endothelial proliferation and smooth muscle cell proliferation, with a potential reduction in apelin-mediated vascular dilatation. miRNA families may act as important pathway components. Increase and decrease of the pathway components in PAH are denoted by upward and downward arrows. The apelin receptor is represented by the cell surface seven-transmembrane receptor in red. Abbreviations: BMPR-II, bone morphogenic protein receptor type II; eNOS, endothelial nitric oxide synthase; FGF2, fibroblast growth factor 2; KLF2, kruppel-like factor 2; NO, nitric oxide; PAH-PAEC, pulmonary arterial endothelial cells in pulmonary arterial hypertension; PASMC, pulmonary arterial smooth muscle cells; PPARγ, peroxisome proliferator-activated receptor γ.