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2-Chlorohexadecanal and 2-Chlorohexadecanoic Acid Induce COX-2 Expression in Human Coronary Artery Endothelial Cells

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Lipids

Abstract

2-Chlorohexadecanal (2-ClHDA), a 16-carbon chain chlorinated fatty aldehyde that is produced by reactive chlorinating species attack of plasmalogens, is elevated in atherosclerotic plaques, infarcted myocardium, and activated leukocytes. We tested the hypothesis that 2-ClHDA and its metabolites, 2-chlorohexadecanoic acid (2-ClHA) and 2-chlorohexadecanol (2-ClHOH), induce COX-2 expression in human coronary artery endothelial cells (HCAEC). COX-2 protein expression increased in response to 2-ClHDA treatments at 8 and 20 h. 2-ClHA also increased COX-2 expression following an 8 h treatment. Quantitative PCR showed that 2-ClHDA treatment increased COX-2 mRNA over 8 h, while 2-ClHA treatment led to a modest increase by 1 h and those levels remained constant over 8 h. 2-ClHDA led to a significant increase in 6-keto-PGF release (a measure of PGI2 release) by HCAEC. These data suggest that 2-ClHDA and its metabolite 2-ClHA, which are produced during leukocyte activation, may alter vascular endothelial cell function by upregulation of COX-2 expression.

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Abbreviations

RCS:

Reactive chlorinating species

2-ClHDA:

2-Chlorohexadecanal

2-ClHA:

2-Chlorohexadecanoic acid

2-ClHOH:

2-Chlorohexadecanol

HDA:

Hexadecanal

COX-2:

Cyclooxygenase-2

NF-κb:

Nuclear factor kappa B

TNF-α:

Tumor necrosis factor-alpha

HCAEC:

Human coronary artery endothelial cells

MPO:

Myeloperoxidase

References

  1. Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P (1999) Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 155:1281–1291

    CAS  PubMed  Google Scholar 

  2. Masferrer JL, Seibert K, Zweifel B, Needleman P (1992) Endogenous glucocorticoids regulate an inducible cyclooxygenase enzyme. Proc Natl Acad Sci USA 89:3917–3921

    Article  CAS  PubMed  Google Scholar 

  3. Kraemer SA, Meade EA, DeWitt DL (1992) Prostaglandin endoperoxide synthase gene structure: identification of the transcriptional start site and 5′-flanking regulatory sequences. Arch Biochem Biophys 293:391–400

    Article  CAS  PubMed  Google Scholar 

  4. Whittaker N, Bunting S, Salmon J, Moncada S, Vane JR, Johnson RA, Morton DR, Kinner JH, Gorman RR, McGuire JC, Sun FF (1976) The chemical structure of prostaglandin X (prostacyclin). Prostaglandins 12:915–928

    Article  CAS  PubMed  Google Scholar 

  5. Moncada S, Gryglewski R, Bunting S, Vane JR (1976) An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263:663–665

    Article  CAS  PubMed  Google Scholar 

  6. Dusting GJ, Moncada S, Vane JR (1977) Prostacyclin (PGX) is the endogenous metabolite responsible for relaxation of coronary arteries induced by arachindonic acid. Prostaglandins 13:3–15

    Article  CAS  PubMed  Google Scholar 

  7. Weksler BB, Marcus AJ, Jaffe EA (1977) Synthesis of prostaglandin I2 (prostacyclin) by cultured human and bovine endothelial cells. Proc Natl Acad Sci USA 74:3922–3926

    Article  CAS  PubMed  Google Scholar 

  8. Willems C, van Aken WG (1979) Production of prostacyclin by vascular endothelial cells. Haemostasis 8:266–273

    CAS  PubMed  Google Scholar 

  9. Jones DA, Carlton DP, McIntyre TM, Zimmerman GA, Prescott SM (1993) Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines. J Biol Chem 268:9049–9054

    CAS  PubMed  Google Scholar 

  10. Daugherty A, Dunn JL, Rateri DL, Heinecke JW (1994) Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 94:437–444

    Article  CAS  PubMed  Google Scholar 

  11. Harrison JE, Schultz J (1976) Studies on the chlorinating activity of myeloperoxidase. J Biol Chem 251:1371–1374

    CAS  PubMed  Google Scholar 

  12. Hazen SL, Hsu FF, Duffin K, Heinecke JW (1996) Molecular chlorine generated by the myeloperoxidase-hydrogen peroxide-chloride system of phagocytes converts low density lipoprotein cholesterol into a family of chlorinated sterols. J Biol Chem 271:23080–23088

    Article  CAS  PubMed  Google Scholar 

  13. Winterbourn CC, van den Berg JJ, Roitman E, Kuypers FA (1992) Chlorohydrin formation from unsaturated fatty acids reacted with hypochlorous acid. Arch Biochem Biophys 296:547–555

    Article  CAS  PubMed  Google Scholar 

  14. Thukkani AK, Hsu FF, Crowley JR, Wysolmerski RB, Albert CJ, Ford DA (2002) Reactive chlorinating species produced during neutrophil activation target tissue plasmalogens: production of the chemoattractant, 2-chlorohexadecanal. J Biol Chem 277:3842–3849

    Article  CAS  PubMed  Google Scholar 

  15. Messner MC, Albert CJ, Hsu FF, Ford DA (2006) Selective plasmenylcholine oxidation by hypochlorous acid: formation of lysophosphatidylcholine chlorohydrins. Chem Phys Lipids 144:34–44

    Article  CAS  PubMed  Google Scholar 

  16. Gross RW (1984) High plasmalogen and arachidonic acid content of canine myocardial sarcolemma: a fast atom bombardment mass spectroscopic and gas chromatography-mass spectroscopic characterization. Biochemistry 23:158–165

    Article  CAS  PubMed  Google Scholar 

  17. Han X, Gross RW (1994) Electrospray ionization mass spectroscopic analysis of human erythrocyte plasma membrane phospholipids. Proc Natl Acad Sci USA 91:10635–10639

    Article  CAS  PubMed  Google Scholar 

  18. Post JA, Verkleij AJ, Roelofsen B, Op de Kamp JA (1988) Plasmalogen content and distribution in the sarcolemma of cultured neonatal rat myocytes. FEBS Lett 240:78–82

    Article  CAS  PubMed  Google Scholar 

  19. Albert CJ, Crowley JR, Hsu FF, Thukkani AK, Ford DA (2001) Reactive chlorinating species produced by myeloperoxidase target the vinyl ether bond of plasmalogens: identification of 2-chlorohexadecanal. J Biol Chem 276:23733–23741

    Article  CAS  PubMed  Google Scholar 

  20. Thukkani AK, Albert CJ, Wildsmith KR, Messner MC, Martinson BD, Hsu FF, Ford DA (2003) Myeloperoxidase-derived reactive chlorinating species from human monocytes target plasmalogens in low density lipoprotein. J Biol Chem 278:36365–36372

    Article  CAS  PubMed  Google Scholar 

  21. Thukkani AK, McHowat J, Hsu FF, Brennan ML, Hazen SL, Ford DA (2003) Identification of alpha-chloro fatty aldehydes and unsaturated lysophosphatidylcholine molecular species in human atherosclerotic lesions. Circulation 108:3128–3133

    Article  CAS  PubMed  Google Scholar 

  22. Thukkani AK, Martinson BD, Albert CJ, Vogler GA, Ford DA (2005) Neutrophil-mediated accumulation of 2-ClHDA during myocardial infarction: 2-ClHDA-mediated myocardial injury. Am J Physiol Heart Circ Physiol 288:H2955–H2964

    Article  CAS  PubMed  Google Scholar 

  23. Marsche G, Heller R, Fauler G, Kovacevic A, Nuszkowski A, Graier W, Sattler W, Malle E (2004) 2-chlorohexadecanal derived from hypochlorite-modified high-density lipoprotein-associated plasmalogen is a natural inhibitor of endothelial nitric oxide biosynthesis. Arterioscler Thromb Vasc Biol 24:2302–2306

    Article  CAS  PubMed  Google Scholar 

  24. Wildsmith KR, Albert CJ, Anbukumar DS, Ford DA (2006) Metabolism of myeloperoxidase-derived 2-chlorohexadecanal. J Biol Chem 281:16849–16860

    Article  CAS  PubMed  Google Scholar 

  25. Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37:911–917

    CAS  PubMed  Google Scholar 

  26. Liu MC, Bleecker ER, Proud D, McLemore TL, Hubbard WC (1988) Profiling of bisenoic prostaglandins and thromboxane B2 in bronchoalveolar fluid from the lower respiratory tract of human subjects by combined capillary gas chromatography-mass spectrometry. Prostaglandins 35:67–79

    Article  CAS  PubMed  Google Scholar 

  27. Schweer H, Kammer J, Seyberth HW (1985) Simultaneous determination of prostanoids in plasma by gas chromatography-negative-ion chemical-ionization mass spectrometry. J Chromatogr 338:273–280

    Article  CAS  PubMed  Google Scholar 

  28. Eligini S, Stella Barbieri S, Cavalca V, Camera M, Brambilla M, De Franceschi M, Tremoli E, Colli S (2005) Diversity and similarity in signaling events leading to rapid Cox-2 induction by tumor necrosis factor-alpha and phorbol ester in human endothelial cells. Cardiovasc Res 65:683–693

    Article  CAS  PubMed  Google Scholar 

  29. Said FA, Werts C, Elalamy I, Couetil JP, Jacquemin C, Hatmi M (2002) TNF-alpha, inefficient by itself, potentiates IL-1beta-induced PGHS-2 expression in human pulmonary microvascular endothelial cells: requirement of NF-kappaB and p38 MAPK pathways. Br J Pharmacol 136:1005–1014

    Article  CAS  PubMed  Google Scholar 

  30. Wu KK (2005) Control of cyclooxygenase-2 transcriptional activation by pro-inflammatory mediators. Prostaglandins Leukot Essent Fatty Acids 72:89–93

    Article  CAS  PubMed  Google Scholar 

  31. Syeda F, Grosjean J, Houliston RA, Keogh RJ, Carter TD, Paleolog E, Wheeler-Jones CP (2006) Cyclooxygenase-2 induction and prostacyclin release by protease-activated receptors in endothelial cells require cooperation between mitogen-activated protein kinase and NF-kappaB pathways. J Biol Chem 281:11792–11804

    Article  CAS  PubMed  Google Scholar 

  32. Chen CC (2006) Signal transduction pathways of inflammatory gene expressions and therapeutic implications. Curr Pharm Des 12:3497–3508

    Article  CAS  PubMed  Google Scholar 

  33. Duque J, Diaz-Munoz MD, Fresno M, Iniguez MA (2006) Up-regulation of cyclooxygenase-2 by interleukin-1beta in colon carcinoma cells. Cell Signal 18:1262–1269

    Article  CAS  PubMed  Google Scholar 

  34. Kumagai T, Matsukawa N, Kaneko Y, Kusumi Y, Mitsumata M, Uchida K (2004) A lipid peroxidation-derived inflammatory mediator: identification of 4-hydroxy-2-nonenal as a potential inducer of cyclooxygenase-2 in macrophages. J Biol Chem 279:48389–48396

    Article  CAS  PubMed  Google Scholar 

  35. Vaillancourt F, Morquette B, Shi Q, Fahmi H, Lavigne P, Di Battista JA, Fernandes JC, Benderdour M (2007) Differential regulation of cyclooxygenase-2 and inducible nitric oxide synthase by 4-hydroxynonenal in human osteoarthritic chondrocytes through ATF-2/CREB-1 transactivation and concomitant inhibition of NF-kappaB signaling cascade. J Cell Biochem 100:1217–1231

    Article  CAS  PubMed  Google Scholar 

  36. Dixon DA, Kaplan CD, McIntyre TM, Zimmerman GA, Prescott SM (2000) Post-transcriptional control of cyclooxygenase-2 gene expression. The role of the 3′-untranslated region. J Biol Chem 275:11750–11757

    Article  CAS  PubMed  Google Scholar 

  37. Inoue H, Taba Y, Miwa Y, Yokota C, Miyagi M, Sasaguri T (2002) Transcriptional and posttranscriptional regulation of cyclooxygenase-2 expression by fluid shear stress in vascular endothelial cells. Arterioscler Thromb Vasc Biol 22:1415–1420

    Article  CAS  PubMed  Google Scholar 

  38. Allport VC, Slater DM, Newton R, Bennett PR (2000) NF-kappaB and AP-1 are required for cyclo-oxygenase 2 gene expression in amnion epithelial cell line (WISH). Mol Hum Reprod 6:561–565

    Article  CAS  PubMed  Google Scholar 

  39. Billack B, Heck DE, Mariano TM, Gardner CR, Sur R, Laskin DL, Laskin JD (2002) Induction of cyclooxygenase-2 by heat shock protein 60 in macrophages and endothelial cells. Am J Physiol Cell Physiol 283:C1267–C1277

    CAS  PubMed  Google Scholar 

  40. Iniguez MA, Martinez-Martinez S, Punzon C, Redondo JM, Fresno M (2000) An essential role of the nuclear factor of activated T cells in the regulation of the expression of the cyclooxygenase-2 gene in human T lymphocytes. J Biol Chem 275:23627–23635

    Article  CAS  PubMed  Google Scholar 

  41. Inoue H, Yokoyama C, Hara S, Tone Y, Tanabe T (1995) Transcriptional regulation of human prostaglandin-endoperoxide synthase-2 gene by lipopolysaccharide and phorbol ester in vascular endothelial cells. Involvement of both nuclear factor for interleukin-6 expression site and cAMP response element. J Biol Chem 270:24965–24971

    Article  CAS  PubMed  Google Scholar 

  42. Kirtikara K, Raghow R, Laulederkind SJ, Goorha S, Kanekura T, Ballou LR (2000) Transcriptional regulation of cyclooxygenase-2 in the human microvascular endothelial cell line, HMEC-1: control by the combinatorial actions of AP2, NF-IL-6 and CRE elements. Mol Cell Biochem 203:41–51

    Article  CAS  PubMed  Google Scholar 

  43. Kosaka T, Miyata A, Ihara H, Hara S, Sugimoto T, Takeda O, Takahashi E, Tanabe T (1994) Characterization of the human gene (PTGS2) encoding prostaglandin-endoperoxide synthase 2. Eur J Biochem 221:889–897

    Article  CAS  PubMed  Google Scholar 

  44. Xu Q, Ji YS, Schmedtje JF Jr. (2000) Sp1 increases expression of cyclooxygenase-2 in hypoxic vascular endothelium. Implications for the mechanisms of aortic aneurysm and heart failure. J Biol Chem 275:24583–24589

    CAS  Google Scholar 

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Correspondence to David A. Ford.

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Messner, M.C., Albert, C.J. & Ford, D.A. 2-Chlorohexadecanal and 2-Chlorohexadecanoic Acid Induce COX-2 Expression in Human Coronary Artery Endothelial Cells. Lipids 43, 581–588 (2008). https://doi.org/10.1007/s11745-008-3189-y

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  • DOI: https://doi.org/10.1007/s11745-008-3189-y

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