Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway

Zhong-jun Du,1 Guan-qun Cui,2 Juan Zhang,1 Xiao-mei Liu,3 Zhi-hu Zhang,1 Qiang Jia,1 Jack C Ng,4 Cheng Peng,1,4 Cun-xiang Bo,1 Hua Shao1 1Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong Academy of Medical Sciences, 2Department of Respiratory Med...

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Autores principales:	Du ZJ, Cui GQ, Zhang J, Liu XM, Zhang ZH, Jia Q, Ng JC, Peng C, Bo CX, Shao H
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	Silica nanoparticles Cardiotoxicity Connexin 43 Cell death Gap junction Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/703c54ffab1f458f9725ea0b1697657f
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spelling	oai:doaj.org-article:703c54ffab1f458f9725ea0b1697657f2021-12-02T00:37:18ZInhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway1178-2013https://doaj.org/article/703c54ffab1f458f9725ea0b1697657f2017-03-01T00:00:00Zhttps://www.dovepress.com/inhibition-of-gap-junction-intercellular-communication-is-involved-in--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Zhong-jun Du,1 Guan-qun Cui,2 Juan Zhang,1 Xiao-mei Liu,3 Zhi-hu Zhang,1 Qiang Jia,1 Jack C Ng,4 Cheng Peng,1,4 Cun-xiang Bo,1 Hua Shao1 1Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong Academy of Medical Sciences, 2Department of Respiratory Medicine, Qilu Children’s Hospital of Shandong University, Jinan, 3Department of Radiation Chemistry and Toxicology, School of Public Health, Jilin University, Changchun, People’s Republic of China; 4National Research Centre for Environmental Toxicology-Entox, The University of Queensland, Brisbane, QLD, Australia Abstract: Gap junction intercellular communication (GJIC) between cardiomyocytes is essential for synchronous heart contraction and relies on connexin-containing channels. Connexin 43 (Cx43) is a major component involved in GJIC in heart tissue, and its abnormal expression is closely associated with various cardiac diseases. Silica nanoparticles (SNPs) are known to induce cardiovascular toxicity. However, the mechanisms through which GJIC plays a role in cardiomyocytes apoptosis induced by SNPs remain unknown. The aim of the present study is to determine whether SNPs-decreased GJIC promotes apoptosis in rat cardiomyocytes cell line (H9c2 cells) via the mitochondrial pathway using CCK-8 Kit, scrape-loading dye transfer technique, Annexin V/PI double-staining assays, and Western blot analysis. The results showed that SNPs elicited cytotoxicity in H9c2 cells in a time- and concentration-dependent manner. SNPs also reduced GJIC in H9c2 cells in a concentration-dependent manner through downregulation of Cx43 and upregulation of P-Cx43. Inhibition of gap junctions by gap junction blocker carbenoxolone disodium resulted in decreased survival and increased apoptosis, whereas enhancement of the gap junctions by retinoic acid led to enhanced survival but decreased apoptosis. Furthermore, SNPs-induced apoptosis through the disrupted functional gap junction was correlated with abnormal expressions of the proteins involved in the mitochondrial pathway-related apoptosis such as Bcl-2/Bax, cytochrome C, Caspase-9, and Caspase-3. Taken together, our results provide the first evidence that SNPs-decreased GJIC promotes apoptosis in cardiomyocytes via the mitochondrial pathway. In addition, downregulation of GJIC by SNPs in cardiomyocytes is mediated through downregulation of Cx43 and upregulation of P-Cx43. These results suggest that in rat cardiomyocytes cell line, GJIC plays a protective role in SNPs-induced apoptosis and that GJIC may be one of the targets for SNPs-induced biological effects. Keywords: silica nanoparticles, cardiotoxicity, connexin 43, cell death, gap junctionDu ZJCui GQZhang JLiu XMZhang ZHJia QNg JCPeng CBo CXShao HDove Medical PressarticleSilica nanoparticlesCardiotoxicityConnexin 43Cell deathGap junctionMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 2179-2188 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Silica nanoparticles Cardiotoxicity Connexin 43 Cell death Gap junction Medicine (General) R5-920
spellingShingle	Silica nanoparticles Cardiotoxicity Connexin 43 Cell death Gap junction Medicine (General) R5-920 Du ZJ Cui GQ Zhang J Liu XM Zhang ZH Jia Q Ng JC Peng C Bo CX Shao H Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway
description	Zhong-jun Du,1 Guan-qun Cui,2 Juan Zhang,1 Xiao-mei Liu,3 Zhi-hu Zhang,1 Qiang Jia,1 Jack C Ng,4 Cheng Peng,1,4 Cun-xiang Bo,1 Hua Shao1 1Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong Academy of Medical Sciences, 2Department of Respiratory Medicine, Qilu Children’s Hospital of Shandong University, Jinan, 3Department of Radiation Chemistry and Toxicology, School of Public Health, Jilin University, Changchun, People’s Republic of China; 4National Research Centre for Environmental Toxicology-Entox, The University of Queensland, Brisbane, QLD, Australia Abstract: Gap junction intercellular communication (GJIC) between cardiomyocytes is essential for synchronous heart contraction and relies on connexin-containing channels. Connexin 43 (Cx43) is a major component involved in GJIC in heart tissue, and its abnormal expression is closely associated with various cardiac diseases. Silica nanoparticles (SNPs) are known to induce cardiovascular toxicity. However, the mechanisms through which GJIC plays a role in cardiomyocytes apoptosis induced by SNPs remain unknown. The aim of the present study is to determine whether SNPs-decreased GJIC promotes apoptosis in rat cardiomyocytes cell line (H9c2 cells) via the mitochondrial pathway using CCK-8 Kit, scrape-loading dye transfer technique, Annexin V/PI double-staining assays, and Western blot analysis. The results showed that SNPs elicited cytotoxicity in H9c2 cells in a time- and concentration-dependent manner. SNPs also reduced GJIC in H9c2 cells in a concentration-dependent manner through downregulation of Cx43 and upregulation of P-Cx43. Inhibition of gap junctions by gap junction blocker carbenoxolone disodium resulted in decreased survival and increased apoptosis, whereas enhancement of the gap junctions by retinoic acid led to enhanced survival but decreased apoptosis. Furthermore, SNPs-induced apoptosis through the disrupted functional gap junction was correlated with abnormal expressions of the proteins involved in the mitochondrial pathway-related apoptosis such as Bcl-2/Bax, cytochrome C, Caspase-9, and Caspase-3. Taken together, our results provide the first evidence that SNPs-decreased GJIC promotes apoptosis in cardiomyocytes via the mitochondrial pathway. In addition, downregulation of GJIC by SNPs in cardiomyocytes is mediated through downregulation of Cx43 and upregulation of P-Cx43. These results suggest that in rat cardiomyocytes cell line, GJIC plays a protective role in SNPs-induced apoptosis and that GJIC may be one of the targets for SNPs-induced biological effects. Keywords: silica nanoparticles, cardiotoxicity, connexin 43, cell death, gap junction
format	article
author	Du ZJ Cui GQ Zhang J Liu XM Zhang ZH Jia Q Ng JC Peng C Bo CX Shao H
author_facet	Du ZJ Cui GQ Zhang J Liu XM Zhang ZH Jia Q Ng JC Peng C Bo CX Shao H
author_sort	Du ZJ
title	Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway
title_short	Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway
title_full	Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway
title_fullStr	Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway
title_full_unstemmed	Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway
title_sort	inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced h9c2 cardiomyocytes apoptosis via the mitochondrial pathway
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/703c54ffab1f458f9725ea0b1697657f
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Inhibition of gap junction intercellular communication is involved in silica nanoparticles-induced H9c2 cardiomyocytes apoptosis via the mitochondrial pathway

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