Avaliação dos efeitos cardiovasculares do novo agonista do receptor MAS, CGEN 856S

Abstract

The increasing evidence of the beneficial effects of Angiotensin-(1-7) [Ang-(1- 7)] through the activation of its receptor Mas, as vasodilation, antiarrhythmogenesis, antitrombogenesis, antifibrogenesis, improvement of erectile dysfunction and lipdic and glicemic metabolism, raised the possibility to develop new drugs based on the ACE2/Ang-(17)/Mas axis. Advances in biotechnology allowed the discovery of a potential Mas agonist, CGEN-856S. This was achieved using a computational biology platform, developed by the biotechnology company Compugen, for predicting novel naturally occurring peptides that may activate G protein-coupled receptors. CGEN-856S was found to activate the Mas receptor, in a cell-based system (Shemesh et al., 2008). In this study we evaluated the cardiovascular effects of this potential Mas agonist, intending to clarify its specificity in binding Mas. CGEN-856S induced an endothelium- and NO-dependent vasodilating effect in aorta rings of mice and rats. The relaxing effect of CGEN-856S was mediated by Mas, as indicated by the lack of action in Mas knockout aortic rings and inhibition by the Mas antagonist, A-779. Our data also show the antiarrhythmogenic effect of CGEN-856S (0,04 nmol/L) in isolated rat hearts. This effect was followed by an improvement of the systolic and diastolic tension during reperfusion, without alterations on the heart rate. CGEN-856S also produced cardio-protection in the isoproterenol-induced heart remodeling model, as demonstrated by a reduction in collagen I, III and fibronectin staining, as well as an anti-hypertrophic effect. The acute (i.v.) and chronic (28 days) administration of CGEN-856S in spontaneously hypertensive rats produced a marked decrease in mean arterial pressure. Radioligand binding competition assay showed that CGEN-856S did not activate AT1 or AT2 Ang II receptors. On the other hand, the CGEN-856S induced an effective displacement of the FAM-Ang-(1-7) binding to CHO Mas-transfected cells. Furthermore, infarcted animals treated with the novel Mas agonist, presented an improvement of cardiac function and a reduction in myocardial infarcted area. These results reinforce the increasing evidence of a key role of Mas in the cardiovascular system. The discovery of CGEN-856S as a novel Mas agonist, might has a therapeutic value and represents an important step for exploration of the effects mediated by Mas and of its potential as a cardiovascular drug target