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The novel Mas agonist, CGEN-856S, attenuates isoproterenol-induced cardiac remodeling and myocardial infarction injury in rats.

Savergnini SQ, Ianzer D, Carvalho MB, Ferreira AJ, Silva GA, Marques FD, Peluso AA, Beiman M, Cojocaru G, Cohen Y, Almeida AP, Rotman G, Santos RA - PLoS ONE (2013)

Bottom Line: CGEN-856S markedly attenuated the MI-induced decrease in systolic tension, as well as in +dT/dt and -dT/dt.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.

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.

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Effects of CGEN-856S and losartan administration on the cardiomyocyte diameters of isoproterenol-treated rats.Animals were treated with isoproterenol (ISO) for 7 days to induce heart hypertrophy or with olive oil as a control. The effects of CGEN-856S were compared to those of saline as a negative control (Veh) or losartan (LOS) as a positive control. Values are expressed as mean ± standard error of the mean (SEM), n = 4−5 animals. *P<0.05 vs. oil +Veh; #P<0.05 vs. ISO+Veh; αP<0.05 vs. ISO+LOS.
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pone-0057757-g001: Effects of CGEN-856S and losartan administration on the cardiomyocyte diameters of isoproterenol-treated rats.Animals were treated with isoproterenol (ISO) for 7 days to induce heart hypertrophy or with olive oil as a control. The effects of CGEN-856S were compared to those of saline as a negative control (Veh) or losartan (LOS) as a positive control. Values are expressed as mean ± standard error of the mean (SEM), n = 4−5 animals. *P<0.05 vs. oil +Veh; #P<0.05 vs. ISO+Veh; αP<0.05 vs. ISO+LOS.

Mentions: The cardiomyocyte cross-sectional area, a measure of cardiac hypertrophy, was significantly increased in ISO + vehicle-treated animals compared to oil + vehicle-treated rats (11.17±0.09 µm vs. 13.91±0.17 µm in ISO + vehicle-treated rats, Figure 1). CGEN-856S treatment reduced the degree of cardiac hypertrophy, as evidenced by a significant decrease in the cardiomyocyte diameter (13.91±0.17 µm vs. 12.41±0.16 µm in ISO + CGEN-856S-treated rats, Figure 1). Losartan administration also attenuated the ISO-induced increase in the cardiomyocyte diameter (13.91±0.17 µm vs. 11.63±0.08 µm in ISO + losartan-treated rats, Figure 1). CGEN-856S or losartan + oil treatment did not significantly affect the cardiomyocyte diameter.


The novel Mas agonist, CGEN-856S, attenuates isoproterenol-induced cardiac remodeling and myocardial infarction injury in rats.

Savergnini SQ, Ianzer D, Carvalho MB, Ferreira AJ, Silva GA, Marques FD, Peluso AA, Beiman M, Cojocaru G, Cohen Y, Almeida AP, Rotman G, Santos RA - PLoS ONE (2013)

Effects of CGEN-856S and losartan administration on the cardiomyocyte diameters of isoproterenol-treated rats.Animals were treated with isoproterenol (ISO) for 7 days to induce heart hypertrophy or with olive oil as a control. The effects of CGEN-856S were compared to those of saline as a negative control (Veh) or losartan (LOS) as a positive control. Values are expressed as mean ± standard error of the mean (SEM), n = 4−5 animals. *P<0.05 vs. oil +Veh; #P<0.05 vs. ISO+Veh; αP<0.05 vs. ISO+LOS.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585977&req=5

pone-0057757-g001: Effects of CGEN-856S and losartan administration on the cardiomyocyte diameters of isoproterenol-treated rats.Animals were treated with isoproterenol (ISO) for 7 days to induce heart hypertrophy or with olive oil as a control. The effects of CGEN-856S were compared to those of saline as a negative control (Veh) or losartan (LOS) as a positive control. Values are expressed as mean ± standard error of the mean (SEM), n = 4−5 animals. *P<0.05 vs. oil +Veh; #P<0.05 vs. ISO+Veh; αP<0.05 vs. ISO+LOS.
Mentions: The cardiomyocyte cross-sectional area, a measure of cardiac hypertrophy, was significantly increased in ISO + vehicle-treated animals compared to oil + vehicle-treated rats (11.17±0.09 µm vs. 13.91±0.17 µm in ISO + vehicle-treated rats, Figure 1). CGEN-856S treatment reduced the degree of cardiac hypertrophy, as evidenced by a significant decrease in the cardiomyocyte diameter (13.91±0.17 µm vs. 12.41±0.16 µm in ISO + CGEN-856S-treated rats, Figure 1). Losartan administration also attenuated the ISO-induced increase in the cardiomyocyte diameter (13.91±0.17 µm vs. 11.63±0.08 µm in ISO + losartan-treated rats, Figure 1). CGEN-856S or losartan + oil treatment did not significantly affect the cardiomyocyte diameter.

Bottom Line: CGEN-856S markedly attenuated the MI-induced decrease in systolic tension, as well as in +dT/dt and -dT/dt.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.

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.

Show MeSH
Related in: MedlinePlus