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Effects of cigarette smoking on cardiovascular-related protein profiles in two community-based cohort studies

  • Biying Huang
    Affiliations
    Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94304, USA

    Department of Medicine, Solna, Karolinska Institutet, 17176 Stockholm, Sweden
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  • Per Svensson
    Affiliations
    Department of Medicine, Solna, Karolinska Institutet, 17176 Stockholm, Sweden
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  • Johan Ärnlöv
    Affiliations
    Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 75185 Uppsala, Sweden

    School of Health and Social Studies, Dalarna University, 79188 Falun, Sweden
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  • Johan Sundström
    Affiliations
    Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 75185 Uppsala, Sweden
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  • Lars Lind
    Affiliations
    Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, 75185 Uppsala, Sweden
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  • Erik Ingelsson
    Correspondence
    Corresponding author. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94304, USA.
    Affiliations
    Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94304, USA

    Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, 75185 Uppsala University, Uppsala, Sweden
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      Highlights

      • Ten cardiovascular-related biomarkers were significantly associated with smoking.
      • The associations were similar in men and women.
      • Associations were consistent in individuals without cardiovascular diseases.
      • Our findings highlight the role of smoking in processes leading to atherosclerosis.

      Abstract

      Background and aims

      Cardiovascular diseases account for the largest fraction of smoking-induced deaths. Studies of smoking in relation to cardiovascular-related protein markers can provide novel insights into the biological effects of smoking. We investigated the associations between cigarette smoking and 80 protein markers known to be related to cardiovascular diseases in two community-based cohorts, the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 969, 50% women, all aged 70 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 717, all men aged 77 years).

      Methods

      Smoking status was self-reported and defined as current smoker, former smoker or never-smoker. Levels of the 80 proteins were measured using the proximity extension assay, a novel PCR-based proteomics technique.

      Results

      We found 30 proteins to be significantly associated with current cigarette smoking in PIVUS (FDR<5%); and ten were replicated in ULSAM (p < 0.05). Matrix metalloproteinase-12 (MMP-12), growth/differentiation factor 15 (GDF-15), urokinase plasminogen activator surface receptor (uPAR), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), lectin-like oxidized LDL receptor 1 (LOX-1), hepatocyte growth factor (HGF), matrix metalloproteinase-10 (MMP-10) and matrix metalloproteinase-1 (MMP-1) were positively associated, while endothelial cell-specific molecule 1 (ESM-1) and interleukin-27 subunit alpha (IL27-A) showed inverse associations. All of them remained significant in a subset of individuals without manifest cardiovascular disease.

      Conclusions

      The findings of the present study suggest that cigarette smoking may interfere with several essential parts of the atherosclerosis process, as evidenced by associations with protein markers representing endothelial dysfunction, inflammation, neointimal formation, foam cell formation and plaque instability.

      Keywords

      Abbreviations:

      CVD (cardiovascular disease), COPD (chronic obstructive pulmonary disease), PEA (proximity extension assay), PIVUS (Prospective Study of the Vasculature in Uppsala Seniors), ULSAM (Uppsala Longitudinal Study of Adult Men), CRP (C-reactive protein), FDR (false discovery rate), MMP-12 (matrix metalloproteinase-12), GDF-15 (growth/differentiation factor 15), UPAR (urokinase plasminogen activator surface receptor), TRAIL-R2 (TNF-related apoptosis-inducing ligand receptor 2), LOX-1 (Lectin-like oxidized LDL receptor 1), HGF (hepatocyte growth factor), MMP-10 (matrix metalloproteinase-10), MMP-1 (matrix metalloproteinase-1), ESM-1 (endothelial cell-specific molecule 1), IL27-A (interleukin-27 subunit alpha), PAD (peripheral artery disease), VSMC (vascular smooth muscle cell), ECM (extracellular matrix)
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      References

      1. Global report: Mortality attributable to tobacco. World Health Organizaion, Geneva2012 (ISBN: 978 92 4 156443 4)
        • Ezzati M.
        • Henley J.
        • Thun M.J.
        • Lopez A.D.
        Role of smoking in global and regional cardiovascular mortality.
        Circulation. 2005; 112: 489-497
        • Csordas A.
        • Bernhard D.
        The biology behind the atherothrombotic effects of cigarette smoke.
        Nat. Rev. Cardiol. 2013; 10: 219-230
        • Plymoth A.
        • Yang Z.
        • Lofdahl C.
        • et al.
        Rapid proteome analysis of bronchoalveolar lavage samples of lifelong smokers and never smokers by micro-scale liquid chromatography and mass spectrometry.
        Clin. Chem. 2006; 52: 671-679
        • Jessie K.
        • Pang W.W.
        • Rahim Z.H.A.
        • Hashim O.H.
        Proteomic analysis of whole human saliva detects enhanced expression of interleukin-1 receptor antagonist, thioredoxin and lipocalin-1 in cigarette smokers compared to non-smokers.
        Int. J. Mol. Sci. 2010; 11: 4488-4505
        • Ohlmeier S.
        • Mazur W.
        • Linja-Aho A.
        • et al.
        Sputum proteomics identifies elevated PIGR levels in smokers and mild-to-moderate COPD.
        J. Proteome Res. 2012; 11: 599-608
        • Titz B.
        • Sewer A.
        • Schneider T.
        • et al.
        Alterations in the sputum proteome and transcriptome in smokers and early-stage COPD subjects.
        J. Proteom. 2015; 128: 306-320
        • Assarsson E.
        • Lundberg M.
        • Holmquist G.
        • et al.
        Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability.
        PLoS One. 2014; 9: e95192
        • Lind L.
        • Fors N.
        • Hall J.
        • Marttala K.
        • Stenborg A.
        A comparison of three different methods to evaluate endothelium-dependent vasodilation in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.
        Arterioscler. Thromb. Vasc. Biol. 2005; 25: 2368-2375
        • Ingelsson E.
        • Sundström J.
        • Arnlöv J.
        • Zethelius B.
        • Lind L.
        Insulin resistance and risk of congestive heart failure.
        JAMA. 2005; 294: 334-341
        • Lundberg M.
        • Eriksson A.
        • Tran B.
        • Assarsson E.
        • Fredriksson S.
        Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood.
        Nucleic Acids Res. 2011; 39: e102
        • Benjamini Y.
        • Hochberg Y.
        Controlling the false ciscovery rate: a practical and powerful approach to multiple testing.
        J. R. Stat. Soc. Ser. B Methodol. 1995; 57: 289-300
        • Ganna A.
        • Salihovic S.
        • Sundstrom J.
        • et al.
        Large-scale metabolomic profiling identifies novel biomarkers for incident coronary heart disease.
        PLoS Genet. 2014; 10: e1004801
        • Ganna A.
        • Lee D.
        • Ingelsson E.
        • Pawitan Y.
        Rediscovery rate estimation for assessing the validation of significant findings in high-throughput studies.
        Brief. Bioinform. 2015; 16: 563-575
        • Lind L.
        • Wallentin L.
        • Kempf T.
        • et al.
        Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study.
        Eur. Heart J. 2009; 30: 2346-2353
        • Sehestedt T.
        • Lyngbæk S.
        • Eugen-Olsen J.
        • et al.
        Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events.
        Atherosclerosis. 2011; 216: 237-243
        • Páramo J.A.
        • Beloqui O.
        • Rodríguez J.A.
        • Diez J.
        • Orbe J.
        Association between matrix metalloproteinase-10 concentration and smoking in individuals without cardiovascular disease.
        Rev. Esp. Cardiol. 2008; 61: 1267-1273
        • Takanabe-Mori R.
        • Ono K.
        • Wada H.
        • et al.
        Lectin-like oxidized low-density lipoprotein receptor-1 plays an important role in vascular inflammation in current smokers.
        J. Atheroscler. Thromb. 2013; 20: 585-590
        • Lieb W.
        • Safa R.
        • Benjamin E.J.
        • et al.
        Vascular endothelial growth factor, its soluble receptor, and hepatocyte growth factor: clinical and genetic correlates and association with vascular function.
        Eur. Heart J. 2009; 30: 1121-1127
        • 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. 2003; 3: 101-117
        • Wu Q.
        • Jiang D.
        • Matsuda J.L.
        • Ternyak K.
        • Zhang B.
        • Chu H.W.
        Cigarette smoke induces human airway epithelial senescence via GDF15 production.
        Am. J. Respir. Cell Mol. Biol. 2016; 55: 429-438
        • Wang Q.
        • Wang Y.
        • Zhang Y.
        • Xiao W.
        The role of uPAR in epithelial-mesenchymal transition in small airway epithelium of patients with chronic obstructive pulmonary disease.
        Respir. Res. 2013; 14: 67
        • Faarvang A.A.
        • Rørdam Preil S.A.
        • Nielsen P.S.
        • Beck H.C.
        • Kristensen L.P.
        • Rasmussen L.M.
        Smoking is associated with lower amounts of arterial type I collagen and decorin.
        Atherosclerosis. 2016; 247: 201-206
        • Della Corte A.
        • Tamburrelli C.
        • Crescente M.
        • et al.
        Platelet proteome in healthy volunteers who smoke.
        Platelets. 2012; 23: 91-105
        • Ho J.E.
        • Mahajan A.
        • Chen M.H.
        • et al.
        Clinical and genetic correlates of growth differentiation factor 15 in the community.
        Clin. Chem. 2012; 58: 1582-1591
        • Orbe J.
        • Montero I.
        • Rodríguez J.A.
        • Beloqui O.
        • Roncal C.
        • Páramo J.A.
        Independent association of matrix metalloproteinase-10, cardiovascular risk factors and subclinical atherosclerosis.
        J. Thromb. Haemost. 2007; 5: 91-97
        • Yilmaz M.I.
        • Siriopol D.
        • Saglam M.
        • et al.
        Plasma endocan levels associate with inflammation, vascular abnormalities, cardiovascular events, and survival in chronic kidney disease.
        Kidney Int. 2014; 86: 1213-1220
        • Scholtes V.P.
        • Johnson J.L.
        • Jenkins N.
        • et al.
        Carotid atherosclerotic plaque matrix metalloproteinase-12-positive macrophage subpopulation predicts adverse outcome after endarterectomy.
        J. Am. Heart Assoc. 2012; 1: e001040
        • Wiklund F.E.
        • Bennet A.M.
        • Magnusson P.K.
        • et al.
        Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality.
        Aging Cell. 2010; 9: 1057-1064
        • Navratilova Z.
        • Kolek V.
        • Petrek M.
        Matrix metalloproteinases and their inhibitors in chronic obstructive pulmonary disease.
        Arch. Immunol. Ther. Exp. Warsz. 2015; 64: 177-193
        • Berezin A.E.
        Diabetes mellitus related biomarker: the predictive role of growth-differentiation factor-15.
        Diabetes Metab. Syndr. 2015; 10S: S154-S157
        • Lind L.
        • Ärnlöv J.
        • Lindahl B.
        • Siegbahn A.
        • Sundström J.
        • Ingelsson E.
        Use of a proximity extension assay proteomics chip to discover new biomarkers for human atherosclerosis.
        Atherosclerosis. 2015; 242: 205-210
        • McDermott M.M.
        • Liu K.
        • Criqui M.H.
        • et al.
        Ankle-brachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis.
        Am. J. Epidemiol. 2005; 162: 33-41
        • Pujades-Rodriguez M.
        • George J.
        • Shah A.D.
        • et al.
        Heterogeneous associations between smoking and a wide range of initial presentations of cardiovascular disease in 1937360 people in England: lifetime risks and implications for risk prediction.
        Int. J. Epidemiol. 2015; 44: 129-141
        • Fukui M.
        • Tanaka M.
        • Senmaru T.
        • et al.
        LOX-1 is a novel marker for peripheral artery disease in patients with type 2 diabetes.
        Metabolism. 2013; 62: 935-938
        • Martinez-Aguilar E.
        • Gomez-Rodriguez V.
        • Orbe J.
        • et al.
        Matrix metalloproteinase 10 is associated with disease severity and mortality in patients with peripheral arterial disease.
        J. Vasc. Surg. 2015; 61: 428-435
        • Mons U.
        • Müezzinler A.
        • Gellert C.
        • et al.
        Impact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium.
        BMJ. 2015; 350: h1551
        • Ambrose J.A.
        • Barua R.S.
        The pathophysiology of cigarette smoking and cardiovascular disease: an update.
        J. Am. Coll. Cardiol. 2004; 43: 1731-1737
        • Pirillo A.
        • Norata G.D.
        • Catapano A.L.
        LOX-1, OxLDL, and atherosclerosis.
        Mediat. Inflamm. 2013; 2013: 152786
        • Ross R.
        Atherosclerosis - an inflammatory disease.
        N. Engl. J. Med. 1999; 340: 115-126
        • Fuhrman B.
        The urokinase system in the pathogenesis of atherosclerosis.
        Atherosclerosis. 2012; 222: 8-14
        • Mayr M.
        • Mayr U.
        • Chung Y.L.
        • Yin X.
        • Griffiths J.R.
        • Xu Q.
        Vascular proteomics: linking proteomic and metabolomic changes.
        Proteomics. 2004; 4: 3751-3761
        • de Jager S.C.
        • Bermúdez B.
        • Bot I.
        • et al.
        Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis.
        J. Exp. Med. 2011; 208: 217-225
        • Balta S.
        • Mikhailidis D.P.
        • Demirkol S.
        • Ozturk C.
        • Celik T.
        • Iyisoy A.
        Endocan: a novel inflammatory indicator in cardiovascular disease?.
        Atherosclerosis. 2015; 243: 339-343
        • Koltsova E.K.
        • Kim G.
        • Lloyd K.M.
        • et al.
        Interleukin-27 receptor limits atherosclerosis in Ldlr-/- mice.
        Circ. Res. 2012; 111: 1274-1285
        • Secchiero P.
        • Zerbinati C.
        • Rimondi E.
        • et al.
        TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells.
        Cell Mol. Life Sci. 2004; 61: 1965-1974
        • Martin-Ventura J.L.
        • Munoz-Garcia B.
        • Egido J.
        • Blanco-Colio L.M.
        Trail and vascular injury.
        Front. Biosci. 2007; 12: 3656-3667
        • Liu F.F.
        • Wu X.
        • Zhang Y.
        • Wang Y.
        • Jiang F.
        TRAIL/DR5 signaling promotes macrophage foam cell formation by modulating scavenger receptor expression.
        PLoS One. 2014; 9: e87059
        • Fu H.
        • Tang Y.Y.
        • Ouyang X.P.
        • et al.
        Interleukin-27 inhibits foam cell formation by promoting macrophage ABCA1 expression through JAK2/STAT3 pathway.
        Biochem. Biophys. Res. Commun. 2014; 452: 881-887
        • Lim C.S.
        • Shalhoub J.
        • Gohel M.S.
        • Shepherd A.C.
        • Davies A.H.
        Matrix metalloproteinases in vascular disease–a potential therapeutic target?.
        Curr. Vasc. Pharmacol. 2010; 8: 75-85
        • Jguirim-Souissi I.
        • Jelassi A.
        • Addad F.
        • et al.
        Plasma metalloproteinase-12 and tissue inhibitor of metalloproteinase-1 levels and presence, severity, and outcome of coronary artery disease.
        Am. J. Cardiol. 2007; 100: 23-27
        • Rajpathak S.N.
        • Wang T.
        • Wassertheil-Smoller S.
        • et al.
        Hepatocyte growth factor and the risk of ischemic stroke developing among postmenopausal women: results from the Women's Health Initiative.
        Stroke. 2010; 41: 857-862
        • Moulton K.S.
        • Vakili K.
        • Zurakowski D.
        • et al.
        Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis.
        Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 4736-4741
        • Leon M.E.
        • Lugo A.
        • Boffetta P.
        • et al.
        Smokeless tobacco use in Sweden and other 17 European countries.
        Eur. J. Public Health. 2016; https://doi.org/10.1093/eurpub/ckw032