Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The biology behind the atherothrombotic effects of cigarette smoke

Abstract

Cigarette smoke is an aerosol that contains >4,000 chemicals, including nicotine, carbon monoxide, acrolein, and oxidant compounds. Exposure to cigarette smoke induces multiple pathological effects in the endothelium, several of which are the result of oxidative stress initiated by reactive oxygen species, reactive nitrogen species, and other oxidant constituents of cigarette smoke. Cigarette-smoke exposure interferes adversely with the control of all stages of plaque formation and development and pathological thrombus formation. The reactive oxygen species in cigarette smoke contribute to oxidative stress, upregulation of inflammatory cytokines, and endothelial dysfunction, by reducing the bioavailability of nitric oxide. Plaque formation and the development of vulnerable plaques also result from exposure to cigarette smoke via the enhancement of inflammatory processes and the activation of matrix metalloproteases. Moreover, exposure to cigarette smoke results in platelet activation, stimulation of the coagulation cascade, and impairment of anticoagulative fibrinolysis. Many cigarette-smoke-mediated prothrombotic changes are quickly reversible upon smoking cessation. Public health efforts should urgently promote our understanding of current cigarette-smoke-induced cardiovascular pathology to encourage individuals to reduce their exposure to cigarette smoke and, therefore, the detrimental consequences of associated atherothrombotic disease.

Key Points

  • A large body of literature strongly suggests that cigarette smoke unfavourably influences all major stages of atherosclerosis as well as pathological atherothrombus formation

  • Cigarette smoke contains oxidant compounds that cause oxidative stress in the endothelium, leading to endothelial dysfunction and injury, initiation of the atherosclerotic process, and subsequent formation of atherosclerotic plaques

  • Cigarette smoke promotes the development of vulnerable plaques and plaque rupture by enhancing inflammation and activating matrix metalloproteinases

  • Cigarette smoke causes platelet activation, and promotes platelet aggregation and platelet adhesion to sites of endothelial injury

  • Exposure to cigarette smoke shifts the balance of haemostasis towards thrombus formation by enhancing blood clotting and, at the same time, reducing the fibrinolytic capacity

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Setting the stage for atherosclerotic plaque formation.
Figure 2
Figure 3: Effects of cigarette smoke (indicated by upward arrows) on coagulatory (blue) and fibrinolytic (orange) pathways.

References

  1. 1

    Ezzati, M., Henley, S. J., Thun, M. J. & Lopez, A. D. Role of smoking in global and regional cardiovascular mortality. Circulation 112, 489–497 (2005).

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Cornel, J. H. et al. Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial. Am. Heart J. 164, 334–342e1 (2012).

    CAS  PubMed  Google Scholar 

  3. 3

    Burke, A. P. et al. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N. Engl. J. Med. 336, 1276–1282 (1997).

    CAS  Google Scholar 

  4. 4

    Pope, C. A. III et al. Cardiovascular mortality and exposure to airborne fine particulate matter and cigarette smoke: shape of the exposure-response relationship. Circulation 120, 941–948 (2009).

    CAS  PubMed  Google Scholar 

  5. 5

    Smith, C. J. & Fischer, T. H. Particulate and vapor phase constituents of cigarette mainstream smoke and risk of myocardial infarction. Atherosclerosis 158, 257–267 (2001).

    CAS  PubMed  Google Scholar 

  6. 6

    Csordas, A., Wick, G., Laufer, G. & Bernhard, D. An evaluation of the clinical evidence on the role of inflammation and oxidative stress in smoking-mediated cardiovascular disease. Biomark. Insights 3, 127–139 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Pryor, W. A. & Stone, K. Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann. NY Acad. Sci. 686, 12–27 (1993).

    CAS  PubMed  Google Scholar 

  8. 8

    Lippi, G., Franchini, M. & Targher, G. Arterial thrombus formation in cardiovascular disease. Nat. Rev. Cardiol. 8, 502–512 (2011).

    PubMed  Google Scholar 

  9. 9

    Fuster, V., Moreno, P. R., Fayad, Z. A., Corti, R. & Badimon, J. J. Atherothrombosis and high-risk plaque: part I: evolving concepts. J. Am. Coll. Cardiol. 46, 937–954 (2005).

    PubMed  PubMed Central  Google Scholar 

  10. 10

    Rahman, M. M. & Laher, I. Structural and functional alteration of blood vessels caused by cigarette smoking: an overview of molecular mechanisms. Curr. Vasc. Pharmacol. 5, 276–292 (2007).

    CAS  PubMed  Google Scholar 

  11. 11

    Zeiher, A. M., Schächinger, V. & Minners, J. Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation 92, 1094–1100 (1995).

    CAS  PubMed  Google Scholar 

  12. 12

    Celermajer, D. S. et al. Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults. N. Engl. J. Med. 334, 150–154 (1996).

    CAS  PubMed  Google Scholar 

  13. 13

    Barua, R. S., Ambrose, J. A., Srivastava, S., DeVoe, M. C. & Eales-Reynolds, L. J. Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation 107, 2342–2347 (2003).

    CAS  PubMed  Google Scholar 

  14. 14

    Jaimes, E. A., DeMaster, E. G., Tian, R. X. & Raij, L. Stable compounds of cigarette smoke induce endothelial superoxide anion production via NADPH oxidase activation. Arterioscler. Thromb. Vasc. Biol. 24, 1031–1036 (2004).

    CAS  PubMed  Google Scholar 

  15. 15

    Kayyali, U. S. et al. Upregulation of xanthine oxidase by tobacco smoke condensate in pulmonary endothelial cells. Toxicol. Appl. Pharmacol. 188, 59–68 (2003).

    CAS  PubMed  Google Scholar 

  16. 16

    Talukder, M. A. et al. Chronic cigarette smoking causes hypertension, increased oxidative stress, impaired NO bioavailability, endothelial dysfunction, and cardiac remodeling in mice. Am. J. Physiol. Heart Circ. Physiol. 300, H388–H396 (2011).

    CAS  PubMed  Google Scholar 

  17. 17

    Frey, R. S., Ushio-Fukai, M. & Malik, A. B. NADPH oxidase-dependent signalling in endothelial cells: role in physiology and pathology. Antioxid. Redox Signal. 11, 791–780 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Li, J. et al. The NADPH oxidase NOX4 drives cardiac differentiation: role in regulating cardiac transcription factors and MAP kinase activation. Mol. Biol. Cell 17, 3978–3988 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Takac, I., Schröder, K. & Brandes, R. P. The Nox family of NADPH oxidases: friend or foe of the vascular system? Curr. Hypertens. Rep. 14, 70–78 (2012).

    CAS  PubMed  Google Scholar 

  20. 20

    Collins, T. Endothelial nuclear factor-κB and the initiation of the atherosclerotic lesion. Lab. Invest. 68, 499–508 (1993).

    CAS  PubMed  Google Scholar 

  21. 21

    Cacciola, R. R., Guarino, F. & Polosa, R. Relevance of endothelial-haemostatic dysfunction in cigarette smoking. Curr. Med. Chem. 14, 1887–1892 (2007).

    CAS  PubMed  Google Scholar 

  22. 22

    Jennings, L. K. Mechanisms of platelet activation: need for new strategies to protect against platelet-mediated atherothrombosis. Thromb. Haemost. 102, 248–257 (2009).

    CAS  PubMed  Google Scholar 

  23. 23

    Ruberg, F. L. & Loscalzo, J. Prothrombotic determinants of coronary atherothrombosis. Vasc. Med. 7, 289–299 (2002).

    PubMed  Google Scholar 

  24. 24

    Bernhard, D. et al. Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules. FASEB J. 19, 1096–1107 (2005).

    CAS  PubMed  Google Scholar 

  25. 25

    Csordas, A. et al. Cigarette smoke extract induces prolonged endoplasmic reticulum stress and autophagic cell death in human umbilical vein endothelial cells. Cardiovasc. Res. 92, 141–148 (2011).

    CAS  PubMed  Google Scholar 

  26. 26

    Falk, E., Shah, P. K. & Fuster, V. Coronary plaque disruption. Circulation 92, 657–671 (1995).

    CAS  Google Scholar 

  27. 27

    Glaser, R. et al. Clinical progression of incidental, asymptomatic lesions discovered during culprit vessel coronary intervention. Circulation 111, 143–149 (2005).

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Wissler, R. W. New insights into the pathogenesis of atherosclerosis as revealed by PDAY. Pathobiological Determinants of Atherosclerosis in Youth. Atherosclerosis 108 (Suppl.), S3–S20 (1994).

    PubMed  Google Scholar 

  29. 29

    Newby, A. C. Metalloproteinases and vulnerable atherosclerotic plaques. Trends Cardiovasc. Med. 17, 253–258 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Shah, P. K. et al. Human monocyte-derived macrophages induce collagen breakdown in fibrous caps of atherosclerotic plaques: potential role of matrix-degrading metalloproteinases and implications for plaque rupture. Circulation 92, 1565–1569 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Nelson, K. K. & Melendez, J. A. Mitochondrial redox control of matrix metalloproteinases. Free Radic. Biol. Med. 37, 768–784 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Perlstein, T. S. & Lee, R. T. Smoking, metalloproteinases, and vascular disease. Arterioscler. Thromb. Vasc. Biol. 26, 250–256 (2006).

    CAS  PubMed  Google Scholar 

  33. 33

    Carty, C. S. et al. Nicotine and cotinine stimulate secretion of basic fibroblast growth factor and affect expression of matrix metalloproteinases in cultured human smooth muscle cells. J. Vasc. Surg. 24, 927–934 (1996).

    CAS  PubMed  Google Scholar 

  34. 34

    Liu, P. Y., Chen, J. H., Li, Y. H., Wu, H. L. & Shi, G. Y. Synergistic effect of stromelysin-1 (matrix metallo-proteinase-3) promoter 5A/6A polymorphism with smoking on the onset of young acute myocardial infarction. Thromb. Haemost. 90, 132–139 (2003).

    CAS  PubMed  Google Scholar 

  35. 35

    Churg, A. et al. α1-Antitrypsin suppresses TNF-α and MMP-12 production by cigarette smoke-stimulated macrophages. Am. J. Respir. Cell Mol. Biol. 37, 144–151 (2007).

    CAS  PubMed  Google Scholar 

  36. 36

    Kangavari, S. et al. Smoking increases inflammation and metalloproteinase expression in human carotid atherosclerotic plaques. J. Cardiovasc. Pharmacol. Ther. 9, 291–298 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Nordskog, B. K., Blixt, A. D., Morgan, W. T., Fields, W. R. & Hellmann, G. M. Matrix-degrading and pro-inflammatory changes in human vascular endothelial cells exposed to cigarette smoke condensate. Cardiovasc. Toxicol. 3, 101–117 (2003).

    PubMed  Google Scholar 

  38. 38

    Wright, J. L., Tai, H., Wang, R., Wang, X. & Churg, A. Cigarette smoke upregulates pulmonary vascular matrix metalloproteinases via TNF-α signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 292, L125–L133 (2007).

    CAS  PubMed  Google Scholar 

  39. 39

    Xue, H. et al. Etanercept attenuates short-term cigarette-smoke-exposure-induced pulmonary arterial remodelling in rats by suppressing the activation of TNF-α/NF-κB signal and the activities of MMP-2 and MMP-9. Pulm. Pharmacol. Ther. 25, 208–215 (2012).

    CAS  PubMed  Google Scholar 

  40. 40

    Vikman, P., Xu, C. B. & Edvinsson, L. Lipid-soluble cigarette smoking particles induce expression of inflammatory and extracellular-matrix-related genes in rat cerebral arteries. Vasc. Health Risk Manag. 5, 333–341 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    O'Toole, T. E. et al. Acrolein activates matrix metalloproteinases by increasing reactive oxygen species in macrophages. Toxicol. Appl. Pharmacol. 236, 194–201 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Lamaître, V., Dabo, A. J. & D'Armiento, J. Cigarette smoke components induce matrix metalloproteinase-1 in aortic endothelial cells through inhibition of mTOR signalling. Toxicol. Sci. 123, 542–549 (2011).

    Google Scholar 

  43. 43

    Oikonen, M. et al. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) in a population of young adults: Relations to cardiovascular risk markers and carotid artery intima–media thickness. The Cardiovascular Risk in Young Finns Study. Scand. J. Clin. Lab. Invest. 72, 540–546 (2012).

    CAS  PubMed  Google Scholar 

  44. 44

    Raveendran, M. et al. Cigarette suppresses the expression of P4Hα and vascular collagen production. Biochem. Biophys. Res. Commun. 323, 592–598 (2004).

    CAS  PubMed  Google Scholar 

  45. 45

    Jorgensen, L. N., Kallehave, F., Christensen, E., Siana, J. E. & Gottrup, F. Less collagen production in smokers. Surgery 123, 450–455 (1998).

    CAS  PubMed  Google Scholar 

  46. 46

    Zhang, K. et al. Interleukin 6 destabilizes atherosclerotic plaques by downregulating prolyl-4-hydroxylase α1 via a mitogen-activated protein kinase and c-Jun pathway. Arch. Biochem. Biophys. 528, 127–133 (2012).

    CAS  PubMed  Google Scholar 

  47. 47

    Bermudez, E. A., Rifai, N., Buring, J. E., Manson, J. E. & Ridker, P. M. Interrelationships among circulating interleukin-6, C-reactive protein, and traditional cardiovascular risk factors in women. Arterioscler. Thromb. Vasc. Biol. 22, 1668–1673 (2002).

    CAS  PubMed  Google Scholar 

  48. 48

    Grundtman, C., Kreutmayer, S. B., Almanzar, G., Wick, M. C. & Wick, G. Heat shock protein 60 and immune inflammatory responses in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 960–968 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Bouki, K. P. et al. Inflammatory markers and plaque morphology: an optical coherence tomography study. Int. J. Cardiol. 154, 287–292 (2012).

    PubMed  Google Scholar 

  50. 50

    van der Wal, A. C., Becker, A. E., van der Loos, C. M. & Das, P. K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89, 36–44 (1994).

    CAS  PubMed  Google Scholar 

  51. 51

    Botti, T. P., Amin, H., Hiltscher, L. & Wissler, R. W. A comparison of the quantitation of macrophage foam cell populations and the extent of apolipoprotein E deposition in developing atherosclerotic lesions in young people: high and low serum thiocyanate groups as an indication of smoking. PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth. Atherosclerosis 124, 191–202 (1996).

    CAS  PubMed  Google Scholar 

  52. 52

    Henderson, B. et al. Cigarette smoke is an endothelial stressor and leads to cell cycle arrest. Atherosclerosis 201, 298–305 (2008).

    CAS  PubMed  Google Scholar 

  53. 53

    Virmani, R. et al. Atherosclerotic plaque progression and vulnerability to rupture: angiogenesis as a source of intraplaque hemorrhage. Arterioscler. Thromb. Vasc. Biol. 25, 2054–2061 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Zhu, B. Q. & Parmley, W. W. Hemodynamic and vascular effects of active and passive smoking. Am. Heart J. 130, 1270–1275 (1995).

    CAS  PubMed  Google Scholar 

  55. 55

    Hung, J., Lam, J. Y., Lacoste, L. & Letchacovski, G. Cigarette smoking acutely increases platelet thrombus formation in patients with coronary artery disease taking aspirin. Circulation 92, 2432–2436 (1995).

    CAS  Google Scholar 

  56. 56

    Winniford, M. D. et al. Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone. Circulation 73, 662–667 (1986).

    CAS  PubMed  Google Scholar 

  57. 57

    Wang, L. X. et al. Coronary spasm, a pathogenic trigger of vulnerable plaque rupture. Chin. Med. J. (Engl.) 124, 4071–4178 (2011).

    Google Scholar 

  58. 58

    Annex, B. H. et al. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 91, 619–622 (1995).

    CAS  PubMed  Google Scholar 

  59. 59

    Toschi, V. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 95, 594–599 (1997).

    CAS  PubMed  Google Scholar 

  60. 60

    Breitenstein, A., Camici, G. G. & Tanner, F. C. Tissue factor: beyond coagulation in the cardiovascular system. Clin. Sci. (Lond.) 118, 159–172 (2010).

    CAS  Google Scholar 

  61. 61

    Sambola, A. et al. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation 107, 973–977 (2003).

    CAS  PubMed  Google Scholar 

  62. 62

    Li, M., Yu, D., Williams, K. J. & Liu, M. L. Tobacco smoke induces the generation of procoagulant microvesicles from human monocytes/macrophages. Arterioscler. Thromb. Vasc. Biol. 30, 1818–1824 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Cirillo, P. et al. Nicotine induces tissue factor expression in cultured endothelial and smooth muscle cells. J. Thromb. Haemost. 4, 453–458 (2006).

    CAS  PubMed  Google Scholar 

  64. 64

    Matetzky, S. et al. Smoking increases tissue factor expression in atherosclerotic plaques: implications for plaque thrombogenicity. Circulation 102, 602–604 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Hölschermann, H. et al. Monocyte tissue factor expression is enhanced in women who smoke and use oral contraceptives. Thromb. Haemost. 82, 1614–1620 (1999).

    PubMed  Google Scholar 

  66. 66

    Heiss, C. et al. Brief secondhand smoke exposure depresses endothelial progenitor cells activity and endothelial function: sustained vascular injury and blunted nitric oxide production. J. Am. Coll. Cardiol. 51, 1760–1771 (2008).

    CAS  PubMed  Google Scholar 

  67. 67

    Kreutmayer, S. B. et al. Dynamics of heat shock protein 60 in endothelial cells exposed to cigarette smoke extract. J. Mol. Cell. Cardiol. 51, 777–780 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Wickenden, J. A. et al. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. Am. J. Respir. Cell Mol. Biol. 29, 562–570 (2003).

    CAS  PubMed  Google Scholar 

  69. 69

    Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Thaulow, E., Erikssen, J., Sandvik, L., Stormorken, H. & Cohn, P. F. Blood platelet count and function are related to total and cardiovascular death in apparently healthy men. Circulation 84, 613–617 (1991).

    CAS  PubMed  Google Scholar 

  71. 71

    Law, M. R. & Wald, N. J. Environmental tobacco smoke and ischemic heart disease. Prog. Cardiovasc. Dis. 46, 31–38 (2003).

    PubMed  Google Scholar 

  72. 72

    Davis, J. W., Shelton, L., Eigenberg, D. A., Hignite, C. E. & Watanabe, I. S. Effects of tobacco and non-tobacco cigarette smoking on endothelium and platelets. Clin. Pharmacol. Ther. 37, 529–533 (1985).

    CAS  PubMed  Google Scholar 

  73. 73

    Imaizumi, T. et al. Effect of cigarette smoking on the levels of platelet-activating factor-like lipid(s) in plasma lipoproteins. Atherosclerosis 87, 47–55 (1991).

    CAS  PubMed  Google Scholar 

  74. 74

    Fusegawa, Y., Goto, S., Handa, S., Kawada, T. & Ando, Y. Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers. Thromb. Res. 93, 271–278 (1999).

    CAS  PubMed  Google Scholar 

  75. 75

    Levine, P. H. An acute effect of cigarette smoking on platelet function: a possible link between smoking and arterial thrombosis. Circulation 48, 619–623 (1973).

    CAS  PubMed  Google Scholar 

  76. 76

    Glynn, M. F., Mustard, J. F., Buchanan, M. R. & Murphy, E. A. Cigarette smoking and platelet aggregation. Can. Med. Assoc. J. 95, 549–553 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Caponnetto, P. et al. Circulating endothelial-coagulative activation markers after smoking cessation: a 12-month observational study. Eur. J. Clin. Invest. 41, 616–626 (2011).

    CAS  PubMed  Google Scholar 

  78. 78

    Blache, D. Involvement of hydrogen and lipid peroxides in acute tobacco smoking-induced platelet hyperactivity. Am. J. Physiol. 268, H679–H685 (1995).

    CAS  PubMed  Google Scholar 

  79. 79

    Lupia, E. et al. Thrombopoietin contributes to enhanced platelet activation in cigarette smokers. Atherosclerosis 210, 314–319 (2010).

    CAS  PubMed  Google Scholar 

  80. 80

    Yarlioglues, M. et al. The acute effects of passive smoking on mean platelet volume in healthy volunteers. Angiology 63, 353–357 (2012).

    PubMed  Google Scholar 

  81. 81

    Sinzinger, H. & Kefalides, A. Passive smoking severely decreases platelet sensitivity to antiaggregatory prostaglandins. Lancet 2, 392–393 (1982).

    CAS  PubMed  Google Scholar 

  82. 82

    Schmid, P. et al. Passive smoking and platelet thromboxane. Thromb. Res. 81, 451–460 (1996).

    CAS  PubMed  Google Scholar 

  83. 83

    Tell, G. S., Grimm, R. H., Vellar, O. D. & Theodorsen, L. The relationship of white cell count, platelet count, and hematocrit to cigarette smoking in adolescents: the Oslo Youth Study. Circulation 72, 971–974 (1985).

    CAS  PubMed  Google Scholar 

  84. 84

    Podrez, E. A. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat. Med. 13, 1086–1095 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Miyaura, S., Eguchi, H. & Johnston, J. M. Effect of a cigarette smoke extract on the metabolism of the proinflammatory autacoid, platelet-activating factor. Circ. Res. 70, 341–347 (1992).

    CAS  PubMed  Google Scholar 

  86. 86

    Marathe, G. K., Prescott, S. M., Zimmerman, G. A. & McIntyre, T. M. Oxidized LDL contains inflammatory PAF-like phospholipids. Trends Cardiovasc. Med. 11, 139–142 (2001).

    CAS  PubMed  Google Scholar 

  87. 87

    Togna, A. R., Latina, V., Orlando, R. & Togna, G. I. Cigarette smoke inhibits adenine nucleotide hydrolysis by human platelets. Platelets 19, 537–542 (2008).

    CAS  PubMed  Google Scholar 

  88. 88

    Ichiki, K., Ikeda, H., Haramaki, N., Ueno, T. & Imaizumi, T. Long-term smoking impairs platelet-derived nitric oxide release. Circulation 94, 3109–3114 (1996).

    CAS  PubMed  Google Scholar 

  89. 89

    Haramaki, N. et al. Long-term smoking causes nitroglycerin resistance in platelets by depletion of intraplatelet glutathione. Arterioscler. Thromb. Vasc. Biol. 21, 1852–1856 (2001).

    CAS  PubMed  Google Scholar 

  90. 90

    Takajo, Y., Ikeda, H., Haramaki, N., Murohara, T. & Imaizumi, T. Augmented oxidative stress of platelets in chronic smokers: mechanisms of impaired platelet-derived nitric oxide bioactivity and augmented platelet aggregability. J. Am. Coll. Cardiol. 38, 1320–1327 (2001).

    CAS  PubMed  Google Scholar 

  91. 91

    Della Corte, A. et al. Platelet proteome in healthy volunteers who smoke. Platelets 23, 91–105 (2012).

    CAS  PubMed  Google Scholar 

  92. 92

    Hennan, J. K. et al. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 104, 820–825 (2001).

    CAS  PubMed  Google Scholar 

  93. 93

    FitzGerald, G. A., Oates, J. A. & Nowak, J. Cigarette smoking and hemostatic function. Am. Heart J. 115, 267–271 (1988).

    CAS  PubMed  Google Scholar 

  94. 94

    Reinders, J. H., Brinkman, H. J., van Mourik, J. A. & de Groot, P. G. Cigarette smoke impairs endothelial cell prostacyclin production. Arteriosclerosis 6, 15–23 (1986).

    CAS  PubMed  Google Scholar 

  95. 95

    Hioki, H. et al. Acute effects of cigarette smoking on platelet-dependent thrombin generation. Eur. Heart J. 22, 56–61 (2001).

    CAS  PubMed  Google Scholar 

  96. 96

    Kimura, S., Nishinaga, M., Ozawa, T. & Shimada, K. Thrombin generation as an acute effect of cigarette smoking. Am. Heart J. 128, 7–11 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Renaud, S., Blache, D., Dumont, E., Thevenon, C. & Wissendanger, T. Platelet function after cigarette smoking in relation to nicotine and carbon monoxide. Clin. Pharmacol. Ther. 36, 389–395 (1984).

    CAS  PubMed  Google Scholar 

  98. 98

    Watts, D. T. The effect of nicotine and smoking on the secretion of epinephrine. Ann. NY Acad. Sci. 90, 74–80 (1960).

    CAS  PubMed  Google Scholar 

  99. 99

    Lande, K., Gjesdal, K., Fønstelien, E., Kjeldsen, S. E. & Eide, I. Effects of adrenaline infusion on platelet number, volume and release reaction. Thromb. Haemost. 54, 450–453 (1985).

    CAS  PubMed  Google Scholar 

  100. 100

    Harding, S. A. et al. Upregulation of the CD40/CD40 ligand dyad and platelet-monocyte aggregation in cigarette smokers. Circulation 109, 1926–1929 (2004).

    CAS  PubMed  Google Scholar 

  101. 101

    Sithu, S. D. et al. Exposure to acrolein by inhalation causes platelet activation. Toxicol. Appl. Pharmacol. 248, 100–110 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Andrè, E. et al. Cigarette smoke-induced neurogenic inflammation is mediated by α,β-unsaturated aldehydes and the TRPA1 receptor in rodents. J. Clin. Invest. 118, 2574–2582 (2008).

    PubMed  PubMed Central  Google Scholar 

  103. 103

    Selley, M. L., Bartlett, M. R., McGuiness, J. A. & Ardlie, N. G. Effects of acrolein on human platelet aggregation. Chem. Biol. Interact. 76, 101–109 (1990).

    CAS  PubMed  Google Scholar 

  104. 104

    Ambrose, J. A. & Barua, R. S. The pathophysiology of cigarette smoking and cardiovascular disease: an update. J. Am. Coll. Cardiol. 43, 1731–1737 (2004).

    CAS  PubMed  Google Scholar 

  105. 105

    Miller, G. J., Bauer, K. A., Cooper, J. A. & Rosenberg, R. D. Activation of the coagulant pathway in cigarette smokers. Thromb. Haemost. 79, 549–553 (1998).

    CAS  PubMed  Google Scholar 

  106. 106

    Markuljak, I., Ivankova, J. & Kubisz, P. Thrombomodulin and von Willebrand factor in smokers and during smoking. Nouv. Rev. Fr. Hematol. 37, 137–139 (1995).

    CAS  PubMed  Google Scholar 

  107. 107

    Raza, S. L., Nehring, L. C., Shapiro, S. D. & Cornelius, L. A. Proteinase-activated receptor-1 regulation of macrophage elastase (MMP-12) secretion by serine proteinases. J. Biol. Chem. 275, 41243–41250 (2000).

    CAS  PubMed  Google Scholar 

  108. 108

    Kwaan, H. C. Role of plasma proteins in whole blood viscosity: a brief clinical review. Clin. Hemorheol. Microcirc. 44, 167–176 (2010).

    CAS  PubMed  Google Scholar 

  109. 109

    Heinrich, J., Balleisen, L., Schulte, H., Assmann, G. & van de Loo, J. Fibrinogen and factor VII in the prediction of coronary PROCAM study in healthy men. Arterioscler. Thromb. 14, 54–59 (1994).

    CAS  PubMed  Google Scholar 

  110. 110

    Tuut, M. & Hense, H. W. Smoking, other risk factors and fibrinogen levels: evidence of effect modification. Ann. Epidemiol. 11, 232–238 (2001).

    CAS  PubMed  Google Scholar 

  111. 111

    Hunter, K. A., Garlick, P. J., Broom, I., Anderson, S. E. & McNurlan, M. A. Effects of smoking and abstention from smoking on fibrinogen synthesis in humans. Clin. Sci. (Lond.) 100, 459–465 (2001).

    CAS  Google Scholar 

  112. 112

    Stone, M. C. & Thorp, J. M. Plasma fibrinogen--a major coronary risk factor. J. R. Coll. Gen. Pract. 35, 565–569 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Tapson, V. F. The role of smoking in coagulation and thromboembolism in chronic obstructive pulmonary disease. Proc. Am. Thorac. Soc. 2, 71–77 (2005).

    CAS  PubMed  Google Scholar 

  114. 114

    Barbash, G. I. et al. Significance of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: experience gleaned from the International Tissue Plasminogen Activator/Streptokinase Mortality trial. Circulation 87, 53–58 (1993).

    CAS  PubMed  Google Scholar 

  115. 115

    Barbash, G. I., White, H. D., Modan, M. & Van der Werf, F. Smoking and acute myocardial infarction. Circulation 87, 1427–1428 (1993).

    CAS  PubMed  Google Scholar 

  116. 116

    Kirtane, A. J. et al. Association of smoking with improved myocardial perfusion and the angiographic characterization of myocardial tissue perfusion after fibrinolytic therapy for ST-segment elevation myocardial infarction. J. Am. Coll. Cardiol. 45, 321–323 (2005).

    PubMed  Google Scholar 

  117. 117

    Barua, R. S. et al. Acute cigarette smoke exposure reduces clot lysis--association between altered fibrin architecture and the response to t-PA. Thromb. Res. 126, 426–430 (2010).

    CAS  PubMed  Google Scholar 

  118. 118

    Pretorius, E., Oberholzer, H. M., van der Spuy, W. J. & Meiring, J. H. Smoking and coagulation: the sticky fibrin phenomenon. Ultrastruct. Pathol. 34, 236–239 (2010).

    PubMed  Google Scholar 

  119. 119

    Shacter, E., Williams, J. A., Lim, M. & Levine, R. L. Differential susceptibility of plasma proteins to oxidative modification: examination by western blot immunoassay. Free Radic. Biol. Med. 17, 429–437 (1994).

    CAS  PubMed  Google Scholar 

  120. 120

    Parahuelva, M. S. et al. Nicotine modulation of factor VII activating protease (FSAP) expression in human monocytes. J. Atheroscler. Thromb. 19, 962–969 (2012).

    Google Scholar 

  121. 121

    van Wersch, J. W., Vooijs, M. E. & Ubachs, J. M. Coagulation factor XIII in pregnant smokers and non-smokers. Int. J. Clin. Lab. Res. 27, 68–71 (1997).

    CAS  PubMed  Google Scholar 

  122. 122

    Allen, R. A., Kluft, C. & Brommer, E. J. Effect of chronic smoking on fibrinolysis. Arteriosclerosis 5, 443–450 (1985).

    CAS  PubMed  Google Scholar 

  123. 123

    Newby, D. E. et al. Impaired coronary tissue plasminogen activator release is associated with coronary atherosclerosis and cigarette smoking: direct link between endothelial dysfunction and atherothrombosis. Circulation 103, 1936–1941 (2001).

    CAS  PubMed  Google Scholar 

  124. 124

    Newby, D. E. et al. Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 99, 1411–1415 (1999).

    CAS  Google Scholar 

  125. 125

    Kaehler, J. et al. Impaired capacity for acute endogenous fibrinolysis in smokers is restored by ascorbic acid. Free Radic. Biol. Med. 44, 315–321 (2008).

    CAS  PubMed  Google Scholar 

  126. 126

    Barua, R. S., Ambrose, J. A., Saha, D. C. & Eales-Reynolds, L. J. Smoking is associated with altered endothelial-derived fibrinolytic and antithrombotic factors: an in vitro demonstration. Circulation 106, 905–908 (2002).

    PubMed  Google Scholar 

  127. 127

    Pellegrini, M. P., Newby, D. E., Maxwell, S. & Webb, D. J. Short-term effects of transdermal nicotine on acute tissue plasminogen activator release in vivo in man. Cardiovasc. Res. 52, 321–327 (2001).

    CAS  PubMed  Google Scholar 

  128. 128

    Zidovetzki, R., Chen, P., Fisher, M., Hofman, F. M. & Faraci, F. M. Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway. Stroke 30, 651–655 (1999).

    CAS  PubMed  Google Scholar 

  129. 129

    Haire, W. D., Goldsmith, J. C. & Rasmussen, J. Abnormal fibrinolysis in healthy male cigarette smokers: role of plasminogen activator inhibitors. Am. J. Hematol. 31, 36–40 (1989).

    CAS  PubMed  Google Scholar 

  130. 130

    Simpson, A. J., Gray, R. S., Moore, N. R. & Booth, N. A. The effects of chronic smoking on the fibrinolytic potential of plasma and platelets. Br. J. Haematol. 97, 208–13 (1997).

    CAS  PubMed  Google Scholar 

  131. 131

    Margaglione, M. et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. Arterioscler. Thromb. Vasc. Biol. 18, 562–567 (1998).

    CAS  PubMed  Google Scholar 

  132. 132

    Tzoulaki, I. et al. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery Study. Circulation 115, 2119–2127 (2007).

    PubMed  Google Scholar 

  133. 133

    Kotani, K., Inata, A. & Araga, S. Hemorheology by microchannel method in males with metabolic syndrome. Arch. Med. Res. 38, 463–464 (2007).

    PubMed  Google Scholar 

  134. 134

    Lowe, G. D., Drummond, M. M., Forbes, C. D. & Barbenel, J. C. The effects of age and cigarette-smoking on blood and plasma viscosity in men. Scott. Med. J. 25, 13–17 (1980).

    CAS  PubMed  Google Scholar 

  135. 135

    Yarnell, J. W. et al. Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease: the Caerphilly and Speedwell collaborative heart disease studies. Circulation 83, 836–844 (1991).

    CAS  PubMed  Google Scholar 

  136. 136

    Haustein, K. O., Krause, J., Haustein, H., Rasmussen, T. & Cort, N. Effects of cigarette smoking or nicotine replacement on cardiovascular risk factors and parameters of haemorheology. J. Intern. Med. 252, 130–139 (2002).

    PubMed  Google Scholar 

  137. 137

    Shimada, S. et al. High blood viscosity is closely associated with cigarette smoking and markedly reduced by smoking cessation. Circ. J. 75, 185–189 (2011).

    PubMed  Google Scholar 

  138. 138

    Price, J. F. et al. Relationship between smoking and cardiovascular risk factors in the development of peripheral arterial disease and coronary artery disease: Edinburgh Artery Study. Eur. Heart J. 20, 344–353 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Ernst, E. Haemorheological consequences of chronic cigarette smoking. J. Cardiovasc. Risk 2, 435–439 (1995).

    CAS  PubMed  Google Scholar 

  140. 140

    Wang, X. L., Sim, A. S., Badenhop, R. F., Mccredie R. M. & Wilcken, D. E. A smoking-dependent risk of coronary artery disease associated with a polymorphism of the endothelial nitric oxidase gene. Nat. Med. 2, 41–45 (1996).

    CAS  PubMed  Google Scholar 

  141. 141

    Ragia, G. et al. Endothelial nitric oxide synthase gene polymorphisms -786T>C and 894G>T in coronary artery bypass graft surgery patients. Hum. Genomics 4, 375–383 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Dzida, G., Sobstyl, J., Pužniak A., Prystupa, A. & Mosiewicz, J. Impact of smoking status on particular genetic polymorphisms associations with cardiovascular diseases. J. Preclin. Clin. Res. 6, 31–34 (2012).

    Google Scholar 

  143. 143

    Lee, C. R. et al. NOS3 polymorphisms, cigarette smoking, and cardiovascular disease. Pharmacogenet. Genomics 16, 891–899 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Nasreen, S. et al. T-786C polymorphism in endothelial NO synthetase gene affects cerebral circulation in smokers: possible gene-environmental interaction. Arterioscler. Thromb. Vasc. Biol. 22, 605–610 (2002).

    CAS  PubMed  Google Scholar 

  145. 145

    Yin, R.-X. et al. Interactions of several lipid-related gene polymorphisms and cigarette smoking on blood pressure levels. Int. J. Biol. Sci. 8, 685–696 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Sen-Banerjee, S., Siles, X. & Campos, H. Tobacco smoke modifies association between Glu-Arg192 polymorphism of human paraxonase gene and risk of myocardial infarction. Atheroscler. Thromb. Vasc. Biol. 20, 2120–2126 (2000).

    CAS  Google Scholar 

  147. 147

    Frey, P. et al. Impact of smoking on cardiovascular events in patients with coronary disease receiving contemporary medical therapy (from the Treating to New Targets [TNT] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] trials). Am. J. Cardiol. 107, 145–150 (2011).

    PubMed  Google Scholar 

Download references

Acknowledgements

D. Bernhard is supported by the Austrian National Bank (Project 14745).

Author information

Affiliations

Authors

Contributions

Both authors were involved in all stages of the manuscript preparation.

Corresponding author

Correspondence to David Bernhard.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Csordas, A., Bernhard, D. The biology behind the atherothrombotic effects of cigarette smoke. Nat Rev Cardiol 10, 219–230 (2013). https://doi.org/10.1038/nrcardio.2013.8

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing