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Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells

Endothelial dysfunction caused by the combined action of disturbed flow, inflammatory mediators and oxidants derived from cigarette smoke is known to promote coronary atherosclerosis and increase the likelihood of myocardial infarctions and strokes. Conversely, laminar flow protects against endothel...

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Main Authors: Teasdale, J.E., Hazell, G.G.J., Peachey, A.M.G., Sala-Newby, G.B., Hindmarch, C.C.T., McKay, T.R., Bond, M., Newby, A.C., White, S.J.
Format: Article
Language:English
Published: Nature Publishing Group 2017
Subjects:
R Medicine
Online Access:http://eprints.um.edu.my/19006/1/Cigarette_smoke_extract_profoundly_suppresses_TNF%CE%B1-mediated_proinflammatory_gene_expression_through_upregulation_of_ATF3_in_human_coronary_artery_endothelial_cells.pdf
http://eprints.um.edu.my/19006/
http://dx.doi.org/10.1038/srep39945
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spelling my.um.eprints.190062018-08-10T07:57:21Z http://eprints.um.edu.my/19006/ Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells Teasdale, J.E. Hazell, G.G.J. Peachey, A.M.G. Sala-Newby, G.B. Hindmarch, C.C.T. McKay, T.R. Bond, M. Newby, A.C. White, S.J. R Medicine Endothelial dysfunction caused by the combined action of disturbed flow, inflammatory mediators and oxidants derived from cigarette smoke is known to promote coronary atherosclerosis and increase the likelihood of myocardial infarctions and strokes. Conversely, laminar flow protects against endothelial dysfunction, at least in the initial phases of atherogenesis. We studied the effects of TNFα and cigarette smoke extract on human coronary artery endothelial cells under oscillatory, normal laminar and elevated laminar shear stress for a period of 72 hours. We found, firstly, that laminar flow fails to overcome the inflammatory effects of TNFα under these conditions but that cigarette smoke induces an anti-oxidant response that appears to reduce endothelial inflammation. Elevated laminar flow, TNFα and cigarette smoke extract synergise to induce expression of the transcriptional regulator activating transcription factor 3 (ATF3), which we show by adenovirus driven overexpression, decreases inflammatory gene expression independently of activation of nuclear factor-κB. Our results illustrate the importance of studying endothelial dysfunction in vitro over prolonged periods. They also identify ATF3 as an important protective factor against endothelial dysfunction. Modulation of ATF3 expression may represent a novel approach to modulate proinflammatory gene expression and open new therapeutic avenues to treat proinflammatory diseases. Nature Publishing Group 2017 Article PeerReviewed application/pdf en http://eprints.um.edu.my/19006/1/Cigarette_smoke_extract_profoundly_suppresses_TNF%CE%B1-mediated_proinflammatory_gene_expression_through_upregulation_of_ATF3_in_human_coronary_artery_endothelial_cells.pdf Teasdale, J.E. and Hazell, G.G.J. and Peachey, A.M.G. and Sala-Newby, G.B. and Hindmarch, C.C.T. and McKay, T.R. and Bond, M. and Newby, A.C. and White, S.J. (2017) Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells. Scientific Reports, 7 (1). ISSN 2045-2322 http://dx.doi.org/10.1038/srep39945 doi:10.1038/srep39945
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
language English
topic R Medicine
spellingShingle R Medicine
Teasdale, J.E.
Hazell, G.G.J.
Peachey, A.M.G.
Sala-Newby, G.B.
Hindmarch, C.C.T.
McKay, T.R.
Bond, M.
Newby, A.C.
White, S.J.
Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells
description Endothelial dysfunction caused by the combined action of disturbed flow, inflammatory mediators and oxidants derived from cigarette smoke is known to promote coronary atherosclerosis and increase the likelihood of myocardial infarctions and strokes. Conversely, laminar flow protects against endothelial dysfunction, at least in the initial phases of atherogenesis. We studied the effects of TNFα and cigarette smoke extract on human coronary artery endothelial cells under oscillatory, normal laminar and elevated laminar shear stress for a period of 72 hours. We found, firstly, that laminar flow fails to overcome the inflammatory effects of TNFα under these conditions but that cigarette smoke induces an anti-oxidant response that appears to reduce endothelial inflammation. Elevated laminar flow, TNFα and cigarette smoke extract synergise to induce expression of the transcriptional regulator activating transcription factor 3 (ATF3), which we show by adenovirus driven overexpression, decreases inflammatory gene expression independently of activation of nuclear factor-κB. Our results illustrate the importance of studying endothelial dysfunction in vitro over prolonged periods. They also identify ATF3 as an important protective factor against endothelial dysfunction. Modulation of ATF3 expression may represent a novel approach to modulate proinflammatory gene expression and open new therapeutic avenues to treat proinflammatory diseases.
format Article
author Teasdale, J.E.
Hazell, G.G.J.
Peachey, A.M.G.
Sala-Newby, G.B.
Hindmarch, C.C.T.
McKay, T.R.
Bond, M.
Newby, A.C.
White, S.J.
author_facet Teasdale, J.E.
Hazell, G.G.J.
Peachey, A.M.G.
Sala-Newby, G.B.
Hindmarch, C.C.T.
McKay, T.R.
Bond, M.
Newby, A.C.
White, S.J.
author_sort Teasdale, J.E.
title Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells
title_short Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells
title_full Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells
title_fullStr Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells
title_full_unstemmed Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells
title_sort cigarette smoke extract profoundly suppresses tnfα-mediated proinflammatory gene expression through upregulation of atf3 in human coronary artery endothelial cells
publisher Nature Publishing Group
publishDate 2017
url http://eprints.um.edu.my/19006/1/Cigarette_smoke_extract_profoundly_suppresses_TNF%CE%B1-mediated_proinflammatory_gene_expression_through_upregulation_of_ATF3_in_human_coronary_artery_endothelial_cells.pdf
http://eprints.um.edu.my/19006/
http://dx.doi.org/10.1038/srep39945
_version_ 1643690858459955200
score 13.211869

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