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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 captopril administration on left ventricular infarct area.(A) Representative photomicrographs and (B) quantification of the infarct area of animals treated with CGEN-856S or captopril. Values are expressed as mean ± SEM, n = 7−8 animals. MI: myocardial infarction. *P<0.05 vs. sham; #P<0.05 vs. MI+vehicle.
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pone-0057757-g004: Effects of CGEN-856S and captopril administration on left ventricular infarct area.(A) Representative photomicrographs and (B) quantification of the infarct area of animals treated with CGEN-856S or captopril. Values are expressed as mean ± SEM, n = 7−8 animals. MI: myocardial infarction. *P<0.05 vs. sham; #P<0.05 vs. MI+vehicle.

Mentions: The cardioprotective actions of CGEN-856S in the ISO model prompted us to study its effects on MI. As shown in Figure 3, MI resulted in reduced systolic tension and decreased velocities of contraction and relaxation (+dT/dt and -dT/dt, respectively) when compared to the sham-operated group. CGEN-856S treatment normalized the systolic tension and attenuated the decrease in the ±dT/dt induced by MI (Figures 3A, 3C, and 3D). In addition, CGEN-856S administration produced a slight but significant increase in the coronary flow when compared with infarcted rats (Figure 3E). No significant changes were observed in the diastolic function or heart rate among the groups (Figures 3B and 3F). The actions of CGEN-856S on the cardiac function of infarcted rats were similar to those effects observed in infarcted rats treated with captopril, an ACE inhibitor used as a positive control (Figure 3). Importantly, CGEN-856S treatment reduced the infarct area when compared to the vehicle-treated group (23.68±1.94% vs. 15.68±3.15% in MI+CGEN-856S-treated rats). In contrast, captopril did not induce any significant effect on the size of the infarct area (Figure 4).


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 captopril administration on left ventricular infarct area.(A) Representative photomicrographs and (B) quantification of the infarct area of animals treated with CGEN-856S or captopril. Values are expressed as mean ± SEM, n = 7−8 animals. MI: myocardial infarction. *P<0.05 vs. sham; #P<0.05 vs. MI+vehicle.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585977&req=5

pone-0057757-g004: Effects of CGEN-856S and captopril administration on left ventricular infarct area.(A) Representative photomicrographs and (B) quantification of the infarct area of animals treated with CGEN-856S or captopril. Values are expressed as mean ± SEM, n = 7−8 animals. MI: myocardial infarction. *P<0.05 vs. sham; #P<0.05 vs. MI+vehicle.
Mentions: The cardioprotective actions of CGEN-856S in the ISO model prompted us to study its effects on MI. As shown in Figure 3, MI resulted in reduced systolic tension and decreased velocities of contraction and relaxation (+dT/dt and -dT/dt, respectively) when compared to the sham-operated group. CGEN-856S treatment normalized the systolic tension and attenuated the decrease in the ±dT/dt induced by MI (Figures 3A, 3C, and 3D). In addition, CGEN-856S administration produced a slight but significant increase in the coronary flow when compared with infarcted rats (Figure 3E). No significant changes were observed in the diastolic function or heart rate among the groups (Figures 3B and 3F). The actions of CGEN-856S on the cardiac function of infarcted rats were similar to those effects observed in infarcted rats treated with captopril, an ACE inhibitor used as a positive control (Figure 3). Importantly, CGEN-856S treatment reduced the infarct area when compared to the vehicle-treated group (23.68±1.94% vs. 15.68±3.15% in MI+CGEN-856S-treated rats). In contrast, captopril did not induce any significant effect on the size of the infarct area (Figure 4).

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