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Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats

We have demonstrated that ATP‐sensitive potassium (K(ATP)) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti‐fibrotic effects of K(ATP) channel agonists were mediate...

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Autores principales: Lee, Tsung‐Ming, Lin, Shinn‐Zong, Chang, Nen‐Chung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783972/
https://www.ncbi.nlm.nih.gov/pubmed/29119680
http://dx.doi.org/10.1111/jcmm.13130
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author Lee, Tsung‐Ming
Lin, Shinn‐Zong
Chang, Nen‐Chung
author_facet Lee, Tsung‐Ming
Lin, Shinn‐Zong
Chang, Nen‐Chung
author_sort Lee, Tsung‐Ming
collection PubMed
description We have demonstrated that ATP‐sensitive potassium (K(ATP)) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti‐fibrotic effects of K(ATP) channel agonists were mediated via regulating macrophage phenotype and fibroblast differentiation by a RhoA/RhoA‐kinase‐dependent pathway. Wistar male rats after induction of myocardial infarction were randomized to either vehicle, nicorandil, an antagonist of K(ATP) channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hrs after infarction. There were similar infarct sizes among the infarcted groups. At day 3 after infarction, post‐infarction was associated with increased RhoA/ROCK activation, which can be inhibited by administering nicorandil. Nicorandil significantly increased myocardial IL‐10 levels and the percentage of regulatory M2 macrophages assessed by immunohistochemical staining, Western blot, and RT‐PCR compared with vehicle. An IL‐10 receptor antibody increased myofibroblast infiltration compared with nicorandil alone. At day 28 after infarction, nicorandil was associated with attenuated cardiac fibrosis. These effects of nicorandil were functionally translated in improved echocardiographically derived cardiac performance. Fasudil showed similarly increased expression of M2 macrophages as nicorandil. The beneficial effects of nicorandil on fibroblast differentiation were blocked by adding glibenclamide. However, glibenclamide cannot abolish the attenuated fibrosis of fasudil, implying that RhoA/RhoA‐kinase is a downstream effector of K(ATP) channel activation. Nicorandil polarized macrophages into M2 phenotype by inhibiting RhoA/RhoA‐kinase pathway, which leads to attenuated myofibroblast‐induced cardiac fibrosis after myocardial infarction.
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spelling pubmed-57839722018-02-08 Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats Lee, Tsung‐Ming Lin, Shinn‐Zong Chang, Nen‐Chung J Cell Mol Med Original Articles We have demonstrated that ATP‐sensitive potassium (K(ATP)) channel agonists attenuated fibrosis; however, the mechanism remained unclear. Since RhoA has been identified as a mediator of cardiac fibrosis, we sought to determine whether the anti‐fibrotic effects of K(ATP) channel agonists were mediated via regulating macrophage phenotype and fibroblast differentiation by a RhoA/RhoA‐kinase‐dependent pathway. Wistar male rats after induction of myocardial infarction were randomized to either vehicle, nicorandil, an antagonist of K(ATP) channel glibenclamide, an antagonist of ROCK fasudil, or a combination of nicorandil and glibenclamide or fasudil and glibenclamide starting 24 hrs after infarction. There were similar infarct sizes among the infarcted groups. At day 3 after infarction, post‐infarction was associated with increased RhoA/ROCK activation, which can be inhibited by administering nicorandil. Nicorandil significantly increased myocardial IL‐10 levels and the percentage of regulatory M2 macrophages assessed by immunohistochemical staining, Western blot, and RT‐PCR compared with vehicle. An IL‐10 receptor antibody increased myofibroblast infiltration compared with nicorandil alone. At day 28 after infarction, nicorandil was associated with attenuated cardiac fibrosis. These effects of nicorandil were functionally translated in improved echocardiographically derived cardiac performance. Fasudil showed similarly increased expression of M2 macrophages as nicorandil. The beneficial effects of nicorandil on fibroblast differentiation were blocked by adding glibenclamide. However, glibenclamide cannot abolish the attenuated fibrosis of fasudil, implying that RhoA/RhoA‐kinase is a downstream effector of K(ATP) channel activation. Nicorandil polarized macrophages into M2 phenotype by inhibiting RhoA/RhoA‐kinase pathway, which leads to attenuated myofibroblast‐induced cardiac fibrosis after myocardial infarction. John Wiley and Sons Inc. 2017-11-09 2018-02 /pmc/articles/PMC5783972/ /pubmed/29119680 http://dx.doi.org/10.1111/jcmm.13130 Text en © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Lee, Tsung‐Ming
Lin, Shinn‐Zong
Chang, Nen‐Chung
Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats
title Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats
title_full Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats
title_fullStr Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats
title_full_unstemmed Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats
title_short Nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of RhoA/Rho‐kinase signalling in infarcted rats
title_sort nicorandil regulates the macrophage skewing and ameliorates myofibroblasts by inhibition of rhoa/rho‐kinase signalling in infarcted rats
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783972/
https://www.ncbi.nlm.nih.gov/pubmed/29119680
http://dx.doi.org/10.1111/jcmm.13130
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