Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Abstract

Abstract-Mas stimulation with angiotensin (Ang)-(1-7) produces cardioprotective effects and vasorelaxation. Using a computational discovery platform for predicting novel naturally occurring peptides that may activate G protein-coupled receptors, we discovered a novel Mas agonist peptide, CGEN-856S. An endothelium-and NO-dependent vasodilating effect was observed for CGEN-856S in thoracic aorta rings of rats (maximal value for the relaxant effect: 39.99Ϯ5.034%), which was similar to that produced by Ang-(1-7) (10 Ϫ10 to 10 Ϫ6 mol/L). In addition, the vasodilator activity of this peptide depended on a functional Mas receptor, because it was abolished in aorta rings of Mas-knockout mice. CGEN-856S appears to bind the Mas receptor at the same binding domain as Ang- (1-7), as suggested by the blocking of its vasorelaxant effect with the Ang-(1-7) analogue D-Ala 7 -Ang-(1-7), and by its competitive inhibition of Ang-(1-7) binding to Mas-transfected cells. The effect of CGEN-856S on reperfusion arrhythmias and cardiac function was studied on ischemia reperfusion of isolated rat hearts. We found that picomolar concentration of CGEN-856S (0.04 nmol/L) had an antiarrhythmogenic effect, as demonstrated by a reduction in the incidence and duration of reperfusion arrhythmias. Furthermore, acute infusion of CGEN-856S produced a shallow dose-dependent decrease in mean arterial pressure of conscious spontaneously hypertensive rats. The maximum change during infusion was observed at the highest dose. Strikingly, blood pressure continued to drop in the postinfusion period. The results presented here indicate that the novel Mas agonist, CGEN-856S, might have a therapeutic value, because it induces vasorelaxing, antihypertensive, and cardioprotective effects. (Hypertension. 2010;56:112-120.)

Angiotensin-converting enzyme 2, angiotensin-(1–7) and Mas: new players of the renin–angiotensin system

“…The endothelium-dependent relaxation induced by Ang-(1-7), AVE 0991 and CGEN-856S in mouse aortic rings is absent in vessels derived from Mas-deficient mice and is blocked by A-779 (Santos et al 2003a, Lemos et al 2005, Savergnini et al 2010. A link between Mas and NO release was described by Pinheiro et al (2004) and Sampaio et al (2007b).…”

“…Taking advantage of this formulation, Marques et al (2011Marques et al ( , 2012 found that chronic oral administration of HPbCD/Ang-(1-7) significantly attenuated the impairment of heart function and cardiac remodeling induced by isoproterenol treatment and myocardial infarction in rats. Furthermore, CGEN-856S, a Mas agonist, promoted antiarrhythmic effects and produced a small dosedependent decrease in arterial pressure in conscious SHR (Savergnini et al 2010). Interestingly, activation of intrinsic ACE2 using the compound XNT improved the cardiac function of spontaneously hypertensive rats (SHR; Hernandez Prada et al 2008) and of diabetic rats (Murca et al 2012a,b).…”

New therapeutic pathways in the RAS

“…27 In animal models CGEN-856 proved to be antihypertensive and anti-arrhythmic. 28 This molecule will now enter clinical development in a collaboration between Compugen 29 and BioLineRx. 30 …”

Angiotensin-(1-7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes?

“…To circumvent the quick degradation, different formulations of Ang 1-7 are being developed e.g. HPβCD/Ang 1-7 (48), NorLeu 3 -A(1-7) (9,49), AVE-0991 (50), cyclic angiotensin 1-7 (http://www.tarixpharma.com, accessed March 06, 2015), CGEN-856 (51). So far, the direct beneficial effects of Ang 1-7 itself are seen in animal models.…”