title: Air pollution upregulates endothelial cell procoagulant activity via ultrafine particle-induced oxidant signaling and tissue factor expression.
abstract: Air pollution exposure is associated with cardiovascular events triggered by clot formation. Endothelial activation and initiation of coagulation are pathophysiological mechanisms that could link inhaled air pollutants to vascular events. Here we investigated the underlying mechanisms of increased endothelial cell procoagulant activity following exposure to soluble components of ultrafine particles (soluble UF). Human coronary artery endothelial cells (HCAEC) were exposed to soluble UF and assessed for their ability to trigger procoagulant activity in platelet-free plasma. Exposed HCAEC triggered earlier thrombin generation and faster fibrin clot formation, which was abolished by an anti-tissue factor (TF) antibody, indicating TF-dependent effects. Soluble UF exposure increased TF mRNA expression without compensatory increases in key anticoagulant proteins. To identify early events that regulate TF expression, we measured endothelial H2O2 production following soluble UF exposure and identified the enzymatic source. Soluble UF exposure increased endothelial H2O2 production, and antioxidants attenuated UF-induced upregulation of TF, linking the procoagulant responses to reactive oxygen species (ROS) formation. Chemical inhibitors and RNA silencing showed that NOX-4, an important endothelial source of H2O2, was involved in UF-induced upregulation of TF mRNA. These data indicate that soluble UF exposure induces endothelial cell procoagulant activity, which involves de novo TF synthesis, ROS production, and the NOX-4 enzyme. These findings provide mechanistic insight into the adverse cardiovascular effects associated with air pollution exposure.
authors.affiliation: Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: S J
authors.initials: SJ
authors.lastname: Snow
authors.affiliation: Department of Environmental Science and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: W
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: A S
authors.initials: AS
authors.lastname: Wolberg
authors.affiliation: Environmental Public Health Division, NHEERL, US Environmental Protection Agency, Research Triangle Park, North Carolina 27599 carraway.martha@epa.gov.
authors.forename: M S
authors.initials: MS
authors.lastname: Carraway
mesh_terms: D000393:Air Pollutants / Q000737:chemistry / Q000633:toxicity*; D018929:Cell Culture Techniques; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010316:Particle Size; D052638:Particulate Matter / Q000737:chemistry / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012995:Solubility; D013917:Thrombin / Q000378:metabolism*; D013925:Thromboplastin / Q000378:metabolism*
chemical_list: D000393:Air Pollutants; D052638:Particulate Matter; D017382:Reactive Oxygen Species; D005337:Fibrin; D013925:Thromboplastin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D013917:Thrombin
keywords: NADPH oxidases; air pollution; reactive oxygen species; thrombin generation; tissue factor
references.citation: Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):233-42
references.pmid: 17951326
references.citation: Environ Health Perspect. 2005 Aug;113(8):1032-8
references.pmid: 16079075
references.citation: Environ Health Perspect. 2010 Jul;118(7):902-8
references.pmid: 20413366
references.citation: Arterioscler Thromb Vasc Biol. 2004 Sep;24(9):1614-20
references.pmid: 15256399
references.citation: Circulation. 2003 Mar 4;107(8):1202-8
references.pmid: 12615802
references.citation: Arterioscler Thromb Vasc Biol. 2007 Aug;27(8):1687-93
references.pmid: 17556654
references.citation: Thromb Res. 2011 Dec;128(6):570-6
references.pmid: 21561645
references.citation: Inhal Toxicol. 2008 Jan;20(2):127-37
references.pmid: 18236227
references.citation: Circulation. 2002 Apr 30;105(17):2030-6
references.pmid: 11980681
references.citation: Int Immunopharmacol. 2008 Oct;8(10):1377-85
references.pmid: 18687299
references.citation: Am J Respir Crit Care Med. 2006 Feb 15;173(4):426-31
references.pmid: 16339922
references.citation: Lancet. 2011 Feb 26;377(9767):732-40
references.pmid: 21353301
references.citation: Circulation. 2006 Dec 5;114(23):2443-8
references.pmid: 17101851
references.citation: Methods Enzymol. 2002;352:220-31
references.pmid: 12125349
references.citation: Toxicol Appl Pharmacol. 2009 Apr 15;236(2):183-93
references.pmid: 19371610
references.citation: Circ Res. 2012 May 11;110(10):1364-90
references.pmid: 22581922
references.citation: Thromb Haemost. 2009 Nov;102(5):936-44
references.pmid: 19888532
references.citation: Thromb Res. 2010 Jan;125(1):90-6
references.pmid: 19345399
references.citation: Nat Chem Biol. 2007 May;3(5):263-7
references.pmid: 17401379
references.citation: Arch Intern Med. 2008 May 12;168(9):920-7
references.pmid: 18474755
references.citation: Environ Health Perspect. 2007 Apr;115(4):535-40
references.pmid: 17450221
references.citation: Circulation. 2002 Jan 29;105(4):411-4
references.pmid: 11815420
references.citation: Blood. 2003 Oct 1;102(7):2678-83
references.pmid: 12805058
references.citation: Cardiovasc Res. 2007 Mar 1;73(4):806-12
references.pmid: 17266944
references.citation: J Occup Environ Med. 2010 Aug;52(8):791-6
references.pmid: 20657302
references.citation: J Aerosol Med. 2004 Summer;17(2):140-52
references.pmid: 15294064
references.citation: Vascul Pharmacol. 2012 May-Jun;56(5-6):216-31
references.pmid: 22405985
references.citation: J Thromb Haemost. 2011 Jul;9(7):1359-67
references.pmid: 21481175
references.citation: Eur Heart J. 2008 Dec;29(24):3043-51
references.pmid: 18952612
references.citation: Environ Health Perspect. 2010 Dec;118(12):1692-8
references.pmid: 20822968
references.citation: J Biomed Mater Res. 1996 Apr;30(4):463-73
references.pmid: 8847354
references.citation: Toxicol Sci. 2007 Jul;98(1):231-9
references.pmid: 17434951
references.citation: N Engl J Med. 2004 Oct 21;351(17):1721-30
references.pmid: 15496621
references.citation: Cancer Epidemiol Biomarkers Prev. 2005 May;14(5):1340-3
references.pmid: 15894700
references.citation: Arch Biochem Biophys. 2005 Aug 15;440(2):123-32
references.pmid: 16036212
references.citation: Arterioscler Thromb Vasc Biol. 2005 Jan;25(1):29-38
references.pmid: 15539615
references.citation: Lab Invest. 1996 Oct;75(4):451-61
references.pmid: 8874378
references.citation: Am J Physiol Cell Physiol. 2006 Aug;291(2):C357-65
references.pmid: 16571865
references.citation: Science. 2005 May 6;308(5723):804-6
references.pmid: 15879201
references.citation: Circulation. 2004 Jan 6;109(1):71-7
references.pmid: 14676145
references.citation: J Thromb Haemost. 2012 Jan;10(1):96-106
references.pmid: 22066779
references.citation: Circ Res. 2008 Mar 14;102(5):589-96
references.pmid: 18202315
references.citation: Indoor Air. 2005 Apr;15(2):141-50
references.pmid: 15737157
references.citation: Blood. 2009 Nov 26;114(23):4886-96
references.pmid: 19797520