title: 4-Hydroxy-2-nonenal enhances tissue factor activity in human monocytic cells via p38 mitogen-activated protein kinase activation-dependent phosphatidylserine exposure.
abstract: OBJECTIVE
  4-hydroxy-2-nonenal (HNE) is one of the major aldehydes formed during lipid peroxidation and is believed to play a role in the pathogenesis of atherosclerosis. The objective of the present study is to investigate the effect of HNE on tissue factor (TF) procoagulant activity expressed on cell surfaces.
  
  
  RESULTS
  TF activity and antigen levels on intact cells were measured using factor Xa generation and TF monoclonal antibody binding assays, respectively. Exposure of phosphatidylserine on the cell surface was analyzed using thrombin generation assay or by binding of a fluorescent dye-conjugated annexin V. 2',7'-dichlorodihydrofluorescein diacetate was used to detect the generation of reactive oxygen species. Our data showed that HNE increased the procoagulant activity of unperturbed THP-1 cells that express traces of TF antigen, but had no effect on unperturbed endothelial cells that express no measurable TF antigen. HNE increased TF procoagulant activity but not TF antigen of both activated monocytic and endothelial cells. HNE treatment generated reactive oxygen species, activated p38 mitogen-activated protein kinase, and increased the exposure of phosphatidylserine at the outer leaflet in THP-1 cells. Treatment of THP-1 cells with an antioxidant, N-acetyl cysteine, suppressed the above HNE-induced responses and negated the HNE-mediated increase in TF activity. Blockade of p38 mitogen-activated protein kinase activation inhibited HNE-induced phosphatidylserine exposure and increased TF activity.
  
  
  CONCLUSIONS
  HNE increases TF coagulant activity in monocytic cells through a novel mechanism involving p38 mitogen-activated protein kinase activation that leads to enhanced phosphatidylserine exposure at the cell surface.
authors: Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, TX 75708, USA. Rit.Vatsyayan@uthct.edu
authors: Rit
authors: R
authors: Vatsyayan
authors: Hema
authors: H
authors: Kothari
authors: Usha R
authors: UR
authors: Pendurthi
authors: L Vijaya Mohan
authors: LV
authors: Rao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000447:Aldehydes / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D015951:Factor Xa / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D018384:Oxidative Stress / Q000187:drug effects; D010718:Phosphatidylserines / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D016207:Cytokines; D008070:Lipopolysaccharides; D010718:Phosphatidylserines; D017382:Reactive Oxygen Species; D013925:Thromboplastin; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D015951:Factor Xa; C027576:4-hydroxy-2-nonenal; D000111:Acetylcysteine
keywords: 4-hydroxy-2-nonenal; atherosclerosis; microparticles; oxidative stress; p38 mitogen-activated protein kinase; tissue factor
references: Free Radic Biol Med. 1998 Dec;25(9):1049-56
references: 9870558
references: Free Radic Biol Med. 2004 Dec 1;37(11):1694-702
references: 15528028
references: FASEB J. 1991 Jul;5(10):2459-65
references: 2065893
references: J Thromb Haemost. 2007 Dec;5(12):2445-52
references: 17922809
references: J Immunol. 1998 Jun 15;160(12):6145-50
references: 9637532
references: Mol Cells. 2011 Dec;32(6):491-509
references: 22207195
references: J Biol Chem. 2006 Nov 17;281(46):35554-66
references: 16982627
references: Arch Biochem Biophys. 2008 Sep 15;477(2):183-95
references: 18602883
references: Cancer Res. 2005 Jun 15;65(12):5365-73
references: 15958585
references: J Biol Chem. 1999 Jan 22;274(4):2234-42
references: 9890986
references: Circulation. 1999 Apr 6;99(13):1753-9
references: 10190887
references: Thromb Haemost. 1995 Jul;74(1):7-17
references: 8578528
references: Proc Natl Acad Sci U S A. 1989 Apr;86(8):2839-43
references: 2704749
references: Arterioscler Thromb. 1994 May;14(5):790-7
references: 8172855
references: Scand J Clin Lab Invest. 1994 Oct;54(6):465-73
references: 7809580
references: Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1015-22
references: 15117736
references: Blood. 1995 Feb 15;85(4):1025-35
references: 7849291
references: Stroke. 1997 Aug;28(8):1557-63
references: 9259748
references: Nat Med. 1996 Jan;2(1):35-40
references: 8564835
references: Thromb Haemost. 1997 Jul;78(1):247-55
references: 9198161
references: Cell Physiol Biochem. 2011;28(6):1279-86
references: 22179015
references: Am J Pathol. 1995 Oct;147(4):1029-40
references: 7573348
references: Toxicol Appl Pharmacol. 2008 Mar 1;227(2):257-64
references: 18096195
references: Front Biosci (Elite Ed). 2012 Jan 01;4:1513-27
references: 22201972
references: J Thromb Haemost. 2011 Apr;9(4):767-75
references: 21320281
references: Circulation. 1996 Dec 15;94(12):3090-7
references: 8989114
references: J Clin Invest. 1989 Oct;84(4):1086-95
references: 2794046
references: J Lipid Mediat Cell Signal. 1995 Jan;11(1):51-61
references: 7728417
references: Chem Phys Lipids. 2009 Jan;157(1):1-11
references: 18977338
references: Thromb Haemost. 1983 Feb 28;49(1):5-7
references: 6845273
references: Prog Lipid Res. 2003 Jul;42(4):318-43
references: 12689622
references: Blood Coagul Fibrinolysis. 1994 Jun;5(3):385-92
references: 8075310
references: J Clin Invest. 1997 Dec 1;100(11):2680-90
references: 9389731
references: J Biol Chem. 1989 Sep 15;264(26):15216-23
references: 2768257
references: Circ Res. 2011 May 13;108(10):1284-97
references: 21566224
references: Thromb Haemost. 1997 Jul;78(1):759-64
references: 9198252
references: Chem Rev. 2011 Oct 12;111(10):5944-72
references: 21861450
references: Free Radic Res. 2010 Oct;44(10):1098-124
references: 20836659
references: Free Radic Biol Med. 2000 Jun 15;28(12):1685-96
references: 10946210
references: Circulation. 1995 Jul 15;92(2):238-43
references: 7600656
references: Free Radic Biol Med. 2004 Sep 1;37(5):607-19
references: 15288119
references: Thromb Res. 2012 Feb;129(2):197-203
references: 21762960
references: Thromb Haemost. 2010 Dec;104(6):1235-41
references: 20886178
references: Cardiovasc Res. 2000 Aug 18;47(3):410-8
references: 10963714
references: Free Radic Res. 2010 Jul;44(7):742-50
references: 20370567
references: Thromb Res. 1990 Jul 15;59(2):421-37
references: 2237820
references: Nat Med. 1996 Feb;2(2):209-15
references: 8574967
references: Circulation. 1997 Feb 4;95(3):594-9
references: 9024145
references: Med Res Rev. 2008 Jul;28(4):569-631
references: 18058921
references: Am J Pathol. 1989 May;134(5):1087-97
references: 2719077
references: Am J Pathol. 1991 Mar;138(3):601-7
references: 2000938
references: J Cell Physiol. 2004 Feb;198(2):230-6
references: 14603525
references: Mol Aspects Med. 2003 Aug-Oct;24(4-5):263-72
references: 12893004
references: J Thromb Haemost. 2009 Apr;7(4):619-26
references: 19187077
references: Free Radic Biol Med. 1992 Oct;13(4):341-90
references: 1398217
references: Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2594-604
references: 16990554
references: Arterioscler Thromb Vasc Biol. 1999 Feb;19(2):384-92
references: 9974423
references: Blood. 2010 Mar 4;115(9):1835-42
references: 19965619
references: Chem Res Toxicol. 1995 Mar;8(2):284-91
references: 7766813
references: Arteriosclerosis. 1989 Jul-Aug;9(4):538-49
references: 2751482
references: Free Radic Biol Med. 2004 Oct 1;37(7):937-45
references: 15336309
references: Lab Invest. 1996 Oct;75(4):451-61
references: 8874378
references: Exp Gerontol. 2009 Oct;44(10):625-33
references: 19622391
references: Br J Pharmacol. 2008 Jan;153(1):6-20
references: 17643134
references: J Am Coll Cardiol. 2007 Feb 20;49(7):772-7
references: 17306706
references: Biochem Pharmacol. 1994 Jul 19;48(2):429-31
references: 8053940
references: Mol Nutr Food Res. 2005 Nov;49(11):1044-9
references: 16270277
references: Am J Pathol. 2007 Nov;171(5):1670-81
references: 17982132
references: IUBMB Life. 2000 Oct-Nov;50(4-5):315-21
references: 11327326
references: J Lab Clin Med. 2000 May;135(5):396-401
references: 10811054
references: J Lipid Res. 2009 Apr;50(4):599-601
references: 19141435
references: Br Med Bull. 1993 Jul;49(3):566-76
references: 8221023
references: Atherosclerosis. 1999 Jun;144(2):273-83
references: 10407489
references: Cardiovasc Res. 2003 Aug 1;59(2):277-87
references: 12909311
references: Circulation. 2000 Feb 29;101(8):841-3
references: 10694520
references: Blood. 2000 Nov 1;96(9):3056-63
references: 11049984
references: Arterioscler Thromb. 1993 Nov;13(11):1689-99
references: 7692957
references: Free Radic Biol Med. 1991;11(1):81-128
references: 1937131
references: Am J Physiol Endocrinol Metab. 2010 Dec;299(6):E879-86
references: 20858748
references: Am Heart J. 1997 Aug;134(2 Pt 1):253-9
references: 9313605