The G Protein Biased Small Molecule Apelin Agonist CMF-019 is Disease Modifying in Endothelial Cell Apoptosis In Vitro and Induces Vasodilatation Without Desensitisation In Vivo

Abstract

Signaling through the apelin receptor is beneficial for a number of diseases including pulmonary arterial hypertension. The endogenous small peptides, apelin and elabela/toddler, are downregulated in pulmonary arterial hypertension but are not suitable for exogenous administration owing to a lack of bioavailability, proteolytic instability and susceptibility to renal clearance. CMF-019, a small molecule apelin agonist that displays strong bias towards G protein signaling over β-arrestin (∼400 fold), may be more suitable. This study demonstrates that in addition to being a positive inotrope, CMF-019 caused dose-dependent vasodilatation in vivo (50 nmol 4.16 ± 1.18 mmHg, **p < 0.01; 500 nmol 6.62 ± 1.85 mmHg, **p < 0.01), without receptor desensitization. Furthermore, CMF-019 rescues human pulmonary artery endothelial cells from apoptosis induced by tumor necrosis factor α and cycloheximide (5.66 ± 0.97%, **p < 0.01) by approximately 50% of that observable with rhVEGF (11.59 ± 1.85%, **p < 0.01), suggesting it has disease-modifying potential in vitro. CMF-019 displays remarkable bias at the apelin receptor for a small molecule and importantly recapitulates all aspects of the cardiovascular responses to the endogenous ligand, [Pyr1]apelin-13, in vivo. Additionally, it is able to protect human pulmonary artery endothelial cells from apoptosis, suggesting that the beneficial effects observed with apelin agonists extend beyond hemodynamic alleviation and address disease etiology itself. These findings support CMF-019 as a G protein biased small molecule apelin agonist in vitro and in vivo that could form the basis for the design of novel therapeutic agents in chronic diseases, such as, pulmonary arterial hypertension.

Apelin-Induced Relaxation of Coronary Arteries is Impaired in a Model of Second-Hand Cigarette Smoke Exposure

“…To further explore the role of the G-protein–independent signaling pathway in the response to apelin in CSE-treated coronary arteries, we compared the effects of apelin with CMF-019, a G-protein biased agonist at APJ receptors. 35 Our data show that, like apelin, CMF-019 causes endothelium-dependent relaxation of isolated rat coronary arteries and that this response is inhibited by the APJ receptor antagonist, F13A. In contrast to apelin, however, CMF-019–induced coronary artery relaxation was unaffected by exposure to CSE.…”

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan

“…Stimulating the apelin pathway offers beneficial vasodilatory haemodynamic effects ( Maguire et al, 2009 ), increases cardiac contractility ( Perjes et al, 2014 ), has been shown to improve cardiac output in PAH patients ( Brash et al, 2018 ), and is suggested to address underlying drivers of PAH disease progression ( Falcao-Pires et al, 2009 ; Alastalo et al, 2011 ; Yang et al, 2017 ; 2019 ). However, a key limitation of apelin agonist therapy is β-arrestin dependent desensitisation of the target apelin receptor, necessitating the identification of G protein-biased ligands that offer better efficacy and cardioprotective effects ( Brame et al, 2015 ; Read et al, 2016 ; 2021 ).…”

(-)-Epicatechin Is a Biased Ligand of Apelin Receptor

“…In the case of the aAPLNR + CMF-019 complex, no hydrogen bond between TM5 and TM7 transmembranal loops was expected, since CMF-019 is known to activate the G protein pathway selectively [ 47 , 53 ]. In addition, in the aAPLNR MD simulation, the hydrogen bonds between the two tyrosine residues of the TM5 and TM7 that are needed for the β-arrestin recruitment are formed [ 41 ], corroborating the idea that EC can recruit β-arrestin in the APLNR active state.…”