The Novel Mas agonist, CGEN-856S, Attenuates Isoproterenol-Induced Cardiac Remodeling and Myocardial Infarction Injury in Rats

Abstract

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.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Ligand treatment with Ang(1-7) or AVE0991 in MAS-transfected cells couples calcium-independent activation of nitric oxide synthase to the phosphatidylinositol 3-kinase/protein kinase B, AKT pathway (Sampaio Verrilli et al, 2012;Savergnini et al, 2013;Than et al, 2013), or activation of phospholipase A2 (Santos et al, 2003b). Ang(1-7) altered the phosphorylation of MAP kinases (Sampaio et al, 2007a;Zimpelmann and Burns, 2009;Liu et al, 2012;Verano-Braga et al, 2012).…”

“…The agonist AR234960 was shown to activate G-protein signaling and the inverse agonist AR244555 selectively inhibited the agonist response as well as the constitutive activity of MAS (Zhang et al, 2012;Tirupula et al, 2014). Remarkably, CGEN-856S is reported to activate calcium and AKT signals (Shemesh et al, 2008;Savergnini et al, 2013). Thus, atypical signaling response suggests functional selectivity of MAS, which allows State of the Angiotensin Receptors interaction with different ligands to activate different signaling pathways, a phenomenon also called biased signaling .…”

New Approaches in the Treatment of Hypertension

“…A cyclic Ang(1-7) analog containing a thioether bridge that makes it resistant to enzymatic digestion and a hydroxypropyl-β-cyclodextrin incorporated Ang(1-7) formulation (HP-β-CD/Ang1-7) have been synthesized and shown to be cardioprotective in animal models of myocardial infarction and insulin resistance/type 2 diabetes [61][62][63] (Table). As an alternative to Ang(1-7), nonpeptide agonists of the Mas receptor, for example, the imidazole compound AVE0991, 64 and novel G-protein-coupled receptor activating peptides, for example, CGEN-856S that have high specificity for the Mas receptor, 65 have been shown to lower BP and protect the vasculature and kidneys in animal models of hypertension and CVD (Table). The relative merits of Mas receptor activation versus ACE2 stimulation are being debated, but all agree that randomized controlled trials in humans with hypertension and related CVDs are needed to assess the therapeutic potential of activating the ACE2/Ang(1-7)/Mas receptor axis.…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…It should be pointed out that all the described effects of Ang-(1-7) or AVE0991 in Mas-transfected cells are related to a Ca 2+ -independent activation of nitric oxide synthase (via the phosphatidylinositol 3-kinase/protein kinase B [AKT] pathway) or to activation of phospholipase A 2 Pinheiro et al, 2004;Sampaio et al, 2007b;Savergnini et al, 2013;Than et al, 2013) (Fig. 4).…”

“…1 mM), such as the agonists MBP7 (Bikkavilli et al, 2006), AR234960 , and CGEN-856S (P61 in Shemesh et al, 2008) with serine instead of cysteine (Savergnini et al, 2010), and the inverse agonist, AR244555 . Interestingly, CGEN-856S has been shown to activate both pathways, Ca 2+ and AKT-but Ca 2+ only in Ga16 transfected cells with a diverted signaling (Shemesh et al, 2008;Savergnini et al, 2013). Thus, the still limited evidence about Mas signaling suggests that Mas behaves like other GPCRs, for which it has also been shown that different ligands activate different signaling pathways, a phenomenon called functional selectivity or biased signaling (Urban et al, 2007;Kenakin and Christopoulos, 2013) (Fig.…”