CGEN-856S is a novel Mas agonist. Herein, we examined the effects of this peptide on isoproterenol (ISO)-induced cardiac remodeling and myocardial infarction (MI) injury. We also sought to determine whether CGEN-856S activates the underlying mechanisms related to Mas receptor activation. Heart hypertrophy and fibrosis were induced by ISO (2 mg·kg−1·day−1) in Wistar rats. After a 7-day treatment period with CGEN-856S (90 µg·kg−1·day−1) or vehicle, the cardiomyocyte diameter was evaluated in left ventricular sections stained with hematoxylin and eosin, and immunofluorescence labeling and quantitative confocal microscopy were used to quantify the deposition of type I and III collagen and fibronectin in the left ventricles. MI was induced by coronary artery ligation, and CGEN-856S (90 µg·kg−1·day−1) or saline was administered for 14 days. The Langendorff technique was used to evaluate cardiac function, and left ventricular sections were stained with Masson’s trichrome dye to quantify the infarct area. Using Chinese hamster ovary cells stably transfected with Mas cDNA, we evaluated whether CGEN-856S alters AKT and endothelial nitric oxide synthase (eNOS) phosphorylation. CGEN-856S reduced the degree of ISO-induced hypertrophy (13.91±0.17 µm vs. 12.41±0.16 µm in the ISO+CGEN-856S group). In addition, the Mas agonist attenuated the ISO-induced increase in collagen I, collagen III, and fibronectin deposition. CGEN-856S markedly attenuated the MI-induced decrease in systolic tension, as well as in +dT/dt and -dT/dt. Furthermore, CGEN-856S administration significantly decreased the infarct area (23.68±2.78% vs. 13.95±4.37% in the MI+CGEN-856S group). These effects likely involved the participation of AKT and NO, as CGEN-856S administration increased the levels of p-AKT and p-eNOS. Thus, our results indicate that CGEN-856S exerts cardioprotective effects on ISO-induced cardiac remodeling and MI-mediated heart failure in rats through a mechanism likely involving the eNOS/AKT pathway.

Abstract-We evaluated the effect of the nonpeptide mimic of angiotensin (Ang)-(1-7), AVE 0991, on the hypotensive effect of bradykinin (BK). Increasing doses of intra-arterial or intravenous BK were administered before and 30 minutes after the beginning of AVE 0991 infusion. The effect of AVE 0991 on plasma Ang-converting enzyme activity was tested using Hip-His-Leu as the substrate. The interaction of AVE 0991 with Ang-converting enzyme in vivo was tested by determining its effect on the pressor action of Ang I or Ang II. AVE 0991 produced a significant and similar potentiation of intra-arterial or intravenous bradykinin. AVE 0991 did not inhibit plasma Ang-converting enzyme activity in vitro or the pressor effect of Ang I in vivo. N W -nitro-L-arginine methyl ester or D-Ala 7 -Ang-(1-7) administration abolished the BK potentiating effect of AVE 0991. We further examined the BK-potentiating effect of AVE 0991, evaluating its effect on NO production in rabbit endothelial cells. The NO release was measured using the 4-amino-5-methylamino-2Ј-7Ј-difluorofluorescein diacetate. A synergistic effect of AVE 0991 and BK on NO release was observed. These results suggest that AVE 0991 potentiates bradykinin through an Ang-converting enzymeindependent, NO-dependent receptor Mas-mediated mechanism. This effect may contribute to the improvement of endothelial function by AVE 0991 in vivo. receptor involved in many of its biological actions 1,2 and of the Ang-converting enzyme (ACE) homologue, ACE 2, as a major Ang-(1-7)-forming enzyme 3,4 gave a more strong support for the concept that Ang-(1-7) is a biologically active component of the renin-Ang system. Furthermore, there is increasing evidence for a role of Ang-(1-7) as a counterregulatory peptide of the cardiovascular effects of Ang II. 2,5 Ang-(1-7) receptor agonists are being considered as putative cardiovascular drugs for the treatment of hypertension, heart failure, atherosclerosis, and many other diseases that involve endothelial dysfunction. 2 Among these compounds AVE 0991, a nonpeptide mimic of Ang-(1-7), 6 has been shown to evoke effects similar to those elicited by Ang-(1-7). 6 -9 In endothelial cells, AVE 0991 releases NO and, to a lesser extent, superoxide. 6 In keeping with the NO-releasing activity of Ang-(1-7) and AVE 0991, 7,8,10 -12 we have shown recently that acute infusion of Ang-(1-7) or AVE 0991 could potentiate the vasodilation produced by intra-arterial acetylcholine, suggesting an improvement of endothelial function. 13 This effect was blocked in the presence of the endothelial NO synthase inhibitor N G -nitro-L-arginine methyl ester (L-NAME) or the receptor Mas antagonist D-Ala 7 -Ang-(1-7) (A-779).Bradykinin (BK) is an endogenous peptide that causes vasodilation depending on endothelial factors, such as NO, the endothelium-derived hyperpolarizing factor, or prostaglandins. 14 Ang-(1-7) enhances the effects of BK in a variety of models. [15][16][17][18][19][20] However, Ang-(1-7) does not directly activate the BK B 2 receptor, 12 but it does amp...