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, DOI https://doi.org/10.1038/srep39945.
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Abstract
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.
| Item Type: | Article |
|---|---|
| Funders: | National Centre for the Replacement Refinement and Reduction of Animals in Research: NC/L001780/1, University of Malaya: High Impact Research Chancellory (UM.C/625/1/HIR/MOHE/MED/22 H-20001-E000086) |
| Uncontrolled Keywords: | Cigarette smoke; Gene expression; Upregulation; ATF3; Human coronary artery endothelial cells |
| Subjects: | R Medicine |
| Divisions: | Faculty of Medicine |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 10 Aug 2018 07:57 |
| Last Modified: | 10 Aug 2018 07:57 |
| URI: | http://eprints.um.edu.my/id/eprint/19006 |
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