Attenuation of isoproterenol-induced cardiac fibrosis in transgenic rats harboring an angiotensin-(1-7)-producing fusion protein in the heart

Ferreira, Anderson J.; Castro, Carlos H.; Guatimosim, Sílvia; Almeida, Paulo Henrique Ribeiro Fernandes; Gomes, Enéas Ricardo de Morais; Peixoto, Marco Fabrício Dias; Alves, Marcia N.; Fagundes-Moura, Cristiane R.; Rentzsch, Brit; Gava, Elisandra; Almeida, Alvair P.; Guimarães, Alexandre M.; Kitten, Gregory T.; Reudelhuber, Timothy L.; Bäder, Michael; Santos, Robson A.S.

doi:10.1177/1753944709353426

Cited by 52 publications

(54 citation statements)

References 34 publications

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“…The accumulating evidence that stimulation of the ACE2/Ang-(1-7)/Mas axis produces cardioprotection and antihypertensive effects 8,19,35,39 raises the possibility of development of a next generation of RAS-related drugs aimed to increase the activity of this axis. 34,41 The results presented here, using CGEN-856S, in addition to reinforcing the concept that Mas stimulation produces beneficial cardiovascular effects, illustrates the potential of this novel therapeutic strategy for treating cardiovascular diseases. …”

Section: Perspectivessupporting

confidence: 70%

“…On the other hand, no evidence for a proarrhytmogenic effect of CGEN-856S (this study) or Ang-(1-7) was obtained in vivo. 3,34 We have also observed an antihypertensive effect of CGEN-856S in SHRs. This observation is in accordance with ongoing studies in our laboratory using Ang-(1-7) 29 and with previous reports by others, suggesting that Mas stimulation could be a strategy to treat hypertension.…”

Section: Discussionmentioning

confidence: 70%

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Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Savergnini

Beiman²,

Lautner³

et al. 2010

Hypertension

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107

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Abstract-Mas stimulation with angiotensin (Ang)-(1-7) produces cardioprotective effects and vasorelaxation. Using a computational discovery platform for predicting novel naturally occurring peptides that may activate G protein-coupled receptors, we discovered a novel Mas agonist peptide, CGEN-856S. An endothelium-and NO-dependent vasodilating effect was observed for CGEN-856S in thoracic aorta rings of rats (maximal value for the relaxant effect: 39.99Ϯ5.034%), which was similar to that produced by Ang-(1-7) (10 Ϫ10 to 10 Ϫ6 mol/L). In addition, the vasodilator activity of this peptide depended on a functional Mas receptor, because it was abolished in aorta rings of Mas-knockout mice. CGEN-856S appears to bind the Mas receptor at the same binding domain as Ang- (1-7), as suggested by the blocking of its vasorelaxant effect with the Ang-(1-7) analogue D-Ala 7 -Ang-(1-7), and by its competitive inhibition of Ang-(1-7) binding to Mas-transfected cells. The effect of CGEN-856S on reperfusion arrhythmias and cardiac function was studied on ischemia reperfusion of isolated rat hearts. We found that picomolar concentration of CGEN-856S (0.04 nmol/L) had an antiarrhythmogenic effect, as demonstrated by a reduction in the incidence and duration of reperfusion arrhythmias. Furthermore, acute infusion of CGEN-856S produced a shallow dose-dependent decrease in mean arterial pressure of conscious spontaneously hypertensive rats. The maximum change during infusion was observed at the highest dose. Strikingly, blood pressure continued to drop in the postinfusion period. The results presented here indicate that the novel Mas agonist, CGEN-856S, might have a therapeutic value, because it induces vasorelaxing, antihypertensive, and cardioprotective effects. (Hypertension. 2010;56:112-120.)

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Section: Perspectivessupporting

confidence: 70%

Section: Discussionmentioning

confidence: 70%

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Savergnini

Beiman²,

Lautner³

et al. 2010

Hypertension

Self Cite

107

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“…In their study Ferreira et al observed no differences in heart rate and blood pressure between transgenic rats, overexpressing Ang(1-7) and control rats (Ferreira et al, 2010). Similar to our findings, there was a decrease in coronary flow in transgenic rats.…”

Section: Discussionsupporting

confidence: 91%

“…In contrast to the present study, Ferreira et al showed an improved cardiac function, indicated by elevated dp/dt anddp/dt and furthermore, an attenuation of the isoproterenolinduced cardiac fibrosis in transgenic rats. Previous studies also indicated an antifibrotic action of Ang(1-7) in vitro and in vivo (Santos et al, 2004;Ferreira et al, 2010;Dong et al, 2012;McCollum et al, 2012;Acuña et al, 2014). In contrast to these findings, the present study revealed no antifibrotic effect of Ang(1-7) in a transgenic rat model.…”

Section: Discussioncontrasting

confidence: 87%

“…Moreover, the CD-induced myocardial fibrosis could not be prevented by an overexpression of Ang(1-7). In their study Ferreira et al used a transgenic rat model, which expressed an Ang(1-7)-producing fusion protein, specifically in the heart, which resulted in a cardiac overexpression of Ang(1-7), whereas the plasma Ang(1-7) concentration remained unchanged (Ferreira et al, 2010). In contrast, our transgenic rat model was generated by an Ang(1-7)-producing fusion protein, expressed in testis, which led to an increase in circulating Ang(1-7) levels (Santos et al, 2004;Schuchard et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Effect of Angiotensin (1-7) on Heart Function in an Experimental Rat Model of Obesity

Blanke¹,

Schlegel²,

Salameh³

et al. 2016

Thorac cardiovasc Surg

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Aim: Obesity is a risk factor for the development of cardiovascular diseases. Recently it was shown that overexpression of the Mas-receptor antagonist angiotensin(1-7) could prevent from diet-induced obesity. However, it remained unclear whether diet-induced obesity and angiotensin(1-7) overexpression might also have effects on the cardiovascular system in these rats.Methods: Twenty three male Sprague Dawley rats were fed with standard chow (SD+chow, n = 5) or a cafeteria diet (SD+CD, n = 6) for 5 months. To investigate the effect of angiotensin(1-7) transgenic rats, expressing an angiotensin(1-7)-producing fusion protein in testis were used. These transgenic rats also received a 5 month's feeding period with either chow (TGR+chow, n = 6) or cafeteria diet (TGR+CD, n = 6), respectively. Hemodynamic measurements (pressure-volume loops) were carried out to assess cardiac function and blood pressure. Subsequently, hearts were explanted and investigated according to the Langendorff technique. Furthermore, cardiac remodeling in these animals was investigated histologically.Results: After 5 months cafeteria diet feeding rats showed a significantly increased body weight, which could be prevented in transgenic rats. However, there was no effect on cardiac performance after cafeteria diet in non-transgenic and transgenic rats. Moreover, overexpression of angiotensin(1-7) deteriorated cardiac contractility as indicated by impaired dp/dt. Furthermore, histological analysis revealed that cafeteria diet led to myocardial fibrosis in both, control and transgenic rats and this was not inhibited by an overproduction of angiotensin(1-7). Conclusion:These results indicate that an overexpression of circulating angiotensin(1-7) prevents a cafeteria diet-induced increase in body weight, but does not affect cardiac performance in this experimental rat model of obesity. Furthermore, overexpression of angiotensin(1-7) alone resulted in an impairment of cardiac function.

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Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

Okita

Nemoto

Yamagata

et al. 2018

European Journal of Pain

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Background We have recently reported that the spinal angiotensin (Ang) converting enzyme (ACE)/Ang II/AT1 receptor axis and downstream p38 MAPK phosphorylation are activated in streptozotocin (STZ)‐induced diabetic mice and lead to tactile hypersensitivity. Moreover, our previous results suggested that the intrathecal (i.t.) administration of Ang (1‐7), an N‐terminal fragment of Ang II, may attenuate the Ang II‐induced nociceptive behaviour through the inhibition of p38 MAPK phosphorylation via Mas receptors. Here, we investigated whether the i.t. administration of Ang (1‐7) can attenuate STZ‐induced diabetic neuropathic pain. Methods Tactile and thermal hypersensitivities were determined using the von Frey filament and Hargreaves tests, respectively. The protein expression of ACE2, Mas receptors and phospho‐p38 MAPK was measured by western blotting. Spinal ACE2 activity was determined using ACE2 activity assay kit. Results The i.t. administration of Ang (1‐7) significantly reduced the tactile and thermal hypersensitivities on day 14 after STZ injection, and these effects were significantly prevented by the Mas receptor antagonist A779. The expression of ACE2 and Mas receptors in the plasma membrane fraction of the lumbar dorsal spinal cord was both significantly decreased in STZ mice. Spinal ACE2 activity was also decreased while p38 MAPK phosphorylation was increased in the lumbar dorsal region of these mice. This phosphorylation was attenuated by the injection of Ang (1‐7), whose effect was reversed by A779. Conclusions Our data demonstrate that Ang (1‐7) attenuates STZ‐induced diabetic neuropathic pain and that this occurs through a mechanism involving spinal Mas receptors and he inhibition of p38 MAPK phosphorylation. Significance The ACE2/Ang (1‐7)/Mas receptor axis was down‐regulated in the spinal cord of STZ mice and the i.t. administration of Ang (1‐7) attenuated the STZ‐induced diabetic neuropathic pain via Mas receptors. Therefore, the activation of this axis could be an effective therapeutic target to alleviate the neuropathic pain in diabetic patients.

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Attenuation of isoproterenol-induced cardiac fibrosis in transgenic rats harboring an angiotensin-(1-7)-producing fusion protein in the heart

Abstract: These results indicate that Ang-(1-7) has blood pressure-independent, antifibrotic effects, acting directly in the heart.

Cited by 52 publications

References 34 publications

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Vascular Relaxation, Antihypertensive Effect, and Cardioprotection of a Novel Peptide Agonist of the Mas Receptor

Effect of Angiotensin (1-7) on Heart Function in an Experimental Rat Model of Obesity

Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

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