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

Signaling through the apelin receptor is beneficial for a number of diseases including pulmonary arterial hypertension. The endogenous small peptides, and elabela/toddler, are downregulated in hypertension but not suitable exogenous administration owing to lack bioavailability, proteolytic instability susceptibility renal clearance. CMF-019, molecule agonist that displays strong bias towards G protein signaling over ?-arrestin (?400 fold), may be more suitable. This study demonstrates addition being positive inotrope, CMF-019 caused dose-dependent vasodilatation vivo (50 nmol 4.16 ± 1.18 mmHg, ** p < 0.01; 500 6.62 1.85 0.01), without desensitization. Furthermore, rescues human artery endothelial cells from apoptosis induced by tumor necrosis factor ? cycloheximide (5.66 0.97%, 0.01) approximately 50% observable with rhVEGF (11.59 1.85%, suggesting it has disease-modifying potential vitro . remarkable at importantly recapitulates all aspects cardiovascular responses ligand, [Pyr 1 ]apelin-13, vivo. Additionally, able protect apoptosis, effects observed agonists extend beyond hemodynamic alleviation address disease etiology itself. These findings support as biased could form basis design novel therapeutic agents chronic diseases, such as,