title: Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells.
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.
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors.forename: Jack E
authors.initials: JE
authors.lastname: Teasdale
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors.forename: Georgina G J
authors.initials: GG
authors.lastname: Hazell
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors.forename: Alasdair M G
authors.initials: AM
authors.lastname: Peachey
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors.forename: Graciela B
authors.initials: GB
authors.lastname: Sala-Newby
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada, K7L 3N6.|Department of Physiology, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: Charles C T
authors.initials: CC
authors.lastname: Hindmarch
authors.affiliation: School of Healthcare Sciences, Manchester Metropolitan University, Manchester M1 5GD, UK.
authors.forename: Tristan R
authors.initials: TR
authors.lastname: McKay
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Bond
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Newby
authors.affiliation: School of Healthcare Sciences, Manchester Metropolitan University, Manchester M1 5GD, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: White
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000975:Antioxidants; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D033081:Shear Strength; D012906:Smoke / Q000009:adverse effects*; D013314:Stress, Mechanical; D014026:Nicotiana; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000975:Antioxidants; D016207:Cytokines; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha