Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.

Cardiac remodeling was shown to be associated with reduced gap junction expression after myocardial infarction. A reduction in gap junctional proteins between myocytes may trigger ventricular arrhythmia. Therefore, we investigated whether N-acetylcysteine exerted antiarrhythmic effect by preserving...

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Autores principales:	Tsung-Ming Lee, Shinn-Zong Lin, Nen-Chung Chang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3c048d4d45e04455a67aba0af1af3f0b
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spelling	oai:doaj.org-article:3c048d4d45e04455a67aba0af1af3f0b2021-11-18T08:57:56ZBoth PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.1932-620310.1371/journal.pone.0071878https://doaj.org/article/3c048d4d45e04455a67aba0af1af3f0b2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24015194/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Cardiac remodeling was shown to be associated with reduced gap junction expression after myocardial infarction. A reduction in gap junctional proteins between myocytes may trigger ventricular arrhythmia. Therefore, we investigated whether N-acetylcysteine exerted antiarrhythmic effect by preserving connexin43 expression in postinfarcted rats, focusing on cAMP downstream molecules such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Male Wistar rats after ligating coronary artery were randomized to either vehicle, or N-acetylcysteine for 4 weeks starting 24 hours after operation. Infarct size was similar between two groups. Compared with vehicle, cAMP levels were increased by N-acetylcysteine treatment after infarction. Myocardial connexin43 expression was significantly decreased in vehicle-treated infarcted rats compared with sham operated rats. Attenuated connexin43 expression and function were blunted after administering N-acetylcysteine, assessed by immunofluorescent analysis, dye coupling, Western blotting, and real-time quantitative RT-PCR of connexin43. Arrhythmic scores during programmed stimulation in the N-acetylcysteine-treated rats were significantly lower than those treated with vehicle. In an ex vivo study, enhanced connexin43 levels afforded by N-acetylcysteine were partially blocked by either H-89 (a PKA inhibitor) or brefeldin A (an Epac-signaling inhibitor) and completely blocked when H-89 and brefeldin A were given in combination. Addition of either the PKA specific activator N6Bz or Epac specific activator 8-CPT did not have additional increased connexin43 levels compared with rats treated with lithium chloride alone. These findings suggest that N-acetylcysteine protects ventricular arrhythmias by attenuating reduced connexin43 expression and function via both PKA- and Epac-dependent pathways, which converge through the inactivation of glycogen synthase kinase-3β.Tsung-Ming LeeShinn-Zong LinNen-Chung ChangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e71878 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tsung-Ming Lee Shinn-Zong Lin Nen-Chung Chang Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.
description	Cardiac remodeling was shown to be associated with reduced gap junction expression after myocardial infarction. A reduction in gap junctional proteins between myocytes may trigger ventricular arrhythmia. Therefore, we investigated whether N-acetylcysteine exerted antiarrhythmic effect by preserving connexin43 expression in postinfarcted rats, focusing on cAMP downstream molecules such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Male Wistar rats after ligating coronary artery were randomized to either vehicle, or N-acetylcysteine for 4 weeks starting 24 hours after operation. Infarct size was similar between two groups. Compared with vehicle, cAMP levels were increased by N-acetylcysteine treatment after infarction. Myocardial connexin43 expression was significantly decreased in vehicle-treated infarcted rats compared with sham operated rats. Attenuated connexin43 expression and function were blunted after administering N-acetylcysteine, assessed by immunofluorescent analysis, dye coupling, Western blotting, and real-time quantitative RT-PCR of connexin43. Arrhythmic scores during programmed stimulation in the N-acetylcysteine-treated rats were significantly lower than those treated with vehicle. In an ex vivo study, enhanced connexin43 levels afforded by N-acetylcysteine were partially blocked by either H-89 (a PKA inhibitor) or brefeldin A (an Epac-signaling inhibitor) and completely blocked when H-89 and brefeldin A were given in combination. Addition of either the PKA specific activator N6Bz or Epac specific activator 8-CPT did not have additional increased connexin43 levels compared with rats treated with lithium chloride alone. These findings suggest that N-acetylcysteine protects ventricular arrhythmias by attenuating reduced connexin43 expression and function via both PKA- and Epac-dependent pathways, which converge through the inactivation of glycogen synthase kinase-3β.
format	article
author	Tsung-Ming Lee Shinn-Zong Lin Nen-Chung Chang
author_facet	Tsung-Ming Lee Shinn-Zong Lin Nen-Chung Chang
author_sort	Tsung-Ming Lee
title	Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.
title_short	Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.
title_full	Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.
title_fullStr	Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.
title_full_unstemmed	Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.
title_sort	both pka and epac pathways mediate n-acetylcysteine-induced connexin43 preservation in rats with myocardial infarction.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/3c048d4d45e04455a67aba0af1af3f0b
work_keys_str_mv	AT tsungminglee bothpkaandepacpathwaysmediatenacetylcysteineinducedconnexin43preservationinratswithmyocardialinfarction AT shinnzonglin bothpkaandepacpathwaysmediatenacetylcysteineinducedconnexin43preservationinratswithmyocardialinfarction AT nenchungchang bothpkaandepacpathwaysmediatenacetylcysteineinducedconnexin43preservationinratswithmyocardialinfarction
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Both PKA and Epac pathways mediate N-acetylcysteine-induced Connexin43 preservation in rats with myocardial infarction.

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