Cargando…

Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor

Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular fun...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Wei-Wei, Bai, Feng, Wang, Jin, Zheng, Rong-Hua, Yang, Li-Wang, James, Erskine A, Zhao, Zhi-Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652925/
https://www.ncbi.nlm.nih.gov/pubmed/29081650
http://dx.doi.org/10.2147/DDDT.S144807
_version_ 1783273153047298048
author Zhang, Wei-Wei
Bai, Feng
Wang, Jin
Zheng, Rong-Hua
Yang, Li-Wang
James, Erskine A
Zhao, Zhi-Qing
author_facet Zhang, Wei-Wei
Bai, Feng
Wang, Jin
Zheng, Rong-Hua
Yang, Li-Wang
James, Erskine A
Zhao, Zhi-Qing
author_sort Zhang, Wei-Wei
collection PubMed
description Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p<0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, p<0.05) and ejection fraction (82%±3% vs 60%±5%, p<0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that edaravone might be selected in combination with other existing drugs in preventing progression of cardiac dysfunction in heart failure.
format Online
Article
Text
id pubmed-5652925
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Dove Medical Press
record_format MEDLINE/PubMed
spelling pubmed-56529252017-10-27 Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor Zhang, Wei-Wei Bai, Feng Wang, Jin Zheng, Rong-Hua Yang, Li-Wang James, Erskine A Zhao, Zhi-Qing Drug Des Devel Ther Original Research Angiotensin II (Ang II) is known to be involved in the progression of ventricular dysfunction and heart failure by eliciting cardiac fibrosis. The purpose of this study was to demonstrate whether treatment with an antioxidant compound, edaravone, reduces cardiac fibrosis and improves ventricular function by inhibiting Ang II AT1 receptor. The study was conducted in a rat model of transverse aortic constriction (TAC). In control, rats were subjected to 8 weeks of TAC. In treated rats, edaravone (10 mg/kg/day) or Ang II AT1 receptor blocker, telmisartan (10 mg/kg/day) was administered by intraperitoneal injection or gastric gavage, respectively, during TAC. Relative to the animals with TAC, edaravone reduced myocardial malonaldehyde level and increased superoxide dismutase activity. Protein level of the AT1 receptor was reduced and the AT2 receptor was upregulated, as evidenced by the reduced ratio of AT1 over AT2 receptor (0.57±0.2 vs 3.16±0.39, p<0.05) and less locally expressed AT1 receptor in the myocardium. Furthermore, the protein level of angiotensin converting enzyme 2 was upregulated. In coincidence with these changes, edaravone significantly decreased the populations of macrophages and myofibroblasts in the myocardium, which were accompanied by reduced levels of transforming growth factor beta 1 and Smad2/3. Collagen I synthesis was inhibited and collagen-rich fibrosis was attenuated. Relative to the TAC group, cardiac systolic function was preserved, as shown by increased left ventricular systolic pressure (204±51 vs 110±19 mmHg, p<0.05) and ejection fraction (82%±3% vs 60%±5%, p<0.05). Treatment with telmisartan provided a comparable level of protection as compared with edaravone in all the parameters measured. Taken together, edaravone treatment ameliorates cardiac fibrosis and improves left ventricular function in the pressure overload rat model, potentially via suppressing the AT1 receptor-mediated signaling pathways. These data indicate that edaravone might be selected in combination with other existing drugs in preventing progression of cardiac dysfunction in heart failure. Dove Medical Press 2017-10-16 /pmc/articles/PMC5652925/ /pubmed/29081650 http://dx.doi.org/10.2147/DDDT.S144807 Text en © 2017 Zhang et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Zhang, Wei-Wei
Bai, Feng
Wang, Jin
Zheng, Rong-Hua
Yang, Li-Wang
James, Erskine A
Zhao, Zhi-Qing
Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor
title Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor
title_full Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor
title_fullStr Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor
title_full_unstemmed Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor
title_short Edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin II AT1 receptor
title_sort edaravone inhibits pressure overload-induced cardiac fibrosis and dysfunction by reducing expression of angiotensin ii at1 receptor
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652925/
https://www.ncbi.nlm.nih.gov/pubmed/29081650
http://dx.doi.org/10.2147/DDDT.S144807
work_keys_str_mv AT zhangweiwei edaravoneinhibitspressureoverloadinducedcardiacfibrosisanddysfunctionbyreducingexpressionofangiotensiniiat1receptor
AT baifeng edaravoneinhibitspressureoverloadinducedcardiacfibrosisanddysfunctionbyreducingexpressionofangiotensiniiat1receptor
AT wangjin edaravoneinhibitspressureoverloadinducedcardiacfibrosisanddysfunctionbyreducingexpressionofangiotensiniiat1receptor
AT zhengronghua edaravoneinhibitspressureoverloadinducedcardiacfibrosisanddysfunctionbyreducingexpressionofangiotensiniiat1receptor
AT yangliwang edaravoneinhibitspressureoverloadinducedcardiacfibrosisanddysfunctionbyreducingexpressionofangiotensiniiat1receptor
AT jameserskinea edaravoneinhibitspressureoverloadinducedcardiacfibrosisanddysfunctionbyreducingexpressionofangiotensiniiat1receptor
AT zhaozhiqing edaravoneinhibitspressureoverloadinducedcardiacfibrosisanddysfunctionbyreducingexpressionofangiotensiniiat1receptor