Abstract 5250: Novel Receptor Mas Peptide Ligands Demonstrate Cardio-Protection and Vascular Relaxation
It has been described that Mas stimulation with angiotensin-(1–7) produces cardioprotective effects and vasorelaxation. Compugen has developed a computational discovery platform for predicting novel naturally-occurring peptides and identifying such peptides that may activate GPCRs. Using this platform, we discovered two peptides: CGEN-856 and CGEN-857, which were found to activate in a cell-based system the Mas receptor, now considered one of the components of the renin-angiotensin system (RAS). These peptides are not related to each other or to angiotensins. Here we tested the cardiovascular effects of CGEN-856 and CGEN-857 in rat animal models (isolated aortic rings, isoproterenol-induced cardiac remodeling and reperfusion arrhythmias). Subnanomolar concentrations of both CGEN-856 and CGEN-857 induced endothelium-dependent vasorelaxation of Wistar rats aortic rings (Emax: 39.99 ± 5.034 and 17.78± 3.43, respectively), and this dose-dependant effect was abolished by a Mas specific antagonist (A-779), indicating that it is mediated through Mas. For induction of heart remodeling, adult Wistar rats (250–300g) were treated with isoproterenol 2mg/Kg/day, subcutaneously, for 7 days. CGEN-856 showed cardio-protection in the Isoproterenol-induced heart remodeling model, as demonstrated by a reduction in Collagen I, Collagen III and Fibronectin staining, as well as an anti-hypertrophic effect on cardiomyocytes. Furthermore, using an ischemia-reperfusion model in rat isolated hearts, we found that picomolar concentration of CGEN-856 had an antiarrhythmogenic effect, as demonstrated by reduction in the incidence and duration of reperfusion arrhythmias. Taken together our results point to a vasorelaxant and cardioprotective function for these novel Mas agonist peptides.