Advertisement

Circulating Wnt inhibitory factor 1 levels are associated with development of cardiovascular disease

  • Claudia Ress
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria

    Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Mariya Paulweber
    Affiliations
    Department of Internal Medicine 1, Paracelsus Private University Salzburg, Salzburg, Austria
    Search for articles by this author
  • Georg Goebel
    Affiliations
    Department of Medical Statistics, Informatics and Health Economics, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Author Footnotes
    1 Present Address: Department of Neurology, Inselspital Bern, Bern, Switzerland.
    Karin Willeit
    Footnotes
    1 Present Address: Department of Neurology, Inselspital Bern, Bern, Switzerland.
    Affiliations
    Department of Internal Medicine 1, Paracelsus Private University Salzburg, Salzburg, Austria
    Search for articles by this author
  • Author Footnotes
    2 Present Address: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
    Kerstin Rufinatscha
    Footnotes
    2 Present Address: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich-Heine University, Düsseldorf, Germany.
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria

    Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Anna Strobl
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Karin Salzmann
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria

    Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Ludmilla Kedenko
    Affiliations
    Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Alexander Tschoner
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Gabriele Staudacher
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Bernhard Iglseder
    Affiliations
    Department of Geriatrics, Paracelsus Private University Salzburg, Salzburg, Austria
    Search for articles by this author
  • Herbert Tilg
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Bernhard Paulweber
    Affiliations
    Department of Internal Medicine 1, Paracelsus Private University Salzburg, Salzburg, Austria
    Search for articles by this author
  • Susanne Kaser
    Correspondence
    Corresponding author. Christian Doppler Laboratory for Metabolic Crosstalk, Department of Internal Medicine I, Medical University Innsbruck, Anichstr. 35, 6020 Innsbruck, Austria.
    Affiliations
    Department of Internal Medicine 1, Medical University Innsbruck, Innsbruck, Austria

    Christian Doppler Laboratory for Metabolic Crosstalk, Medical University Innsbruck, Innsbruck, Austria
    Search for articles by this author
  • Author Footnotes
    1 Present Address: Department of Neurology, Inselspital Bern, Bern, Switzerland.
    2 Present Address: Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich-Heine University, Düsseldorf, Germany.

      Highlights

      • Increased SFRP-1 and WIF-1 levels precede future cardiovascular events in subjects without overt cardiovascular disease.
      • Logistic regression analysis revealed WIF-1 as a significant predictor of future cardiovascular events.
      • Increased SFRP-1 and WIF-1 levels might reflect altered Wnt signaling in early atherogenesis.
      • Assessment of WIF-1 might help to identify patients at very high cardiovascular risk at an early stage.

      Abstract

      Background and aims

      Wnt signaling is involved in atherosclerotic plaque formation directly and indirectly by modulating cardiovascular risk factors. We investigated whether circulating concentrations of Wnt inhibitors are associated with cardiovascular events in subjects with intermediate cardiovascular risk.

      Methods

      904 non-diabetic subjects participating in the SAPHIR study were assessed. In the SAPHIR study, middle-aged women without overt atherosclerotic disease at study entry were followed up for 10 years. 88 patients of our study cohort developed cardiovascular disease at follow-up (CVD group). Subjects of the CVD group were 1:2 case-control matched for age, sex, BMI and smoking behavior with subjects without overt cardiovascular disease after a 10 year-follow-up (control group). 18 patients of the CVD group and 19 subjects of the control group were retrospectively excluded due to fulfilling exclusion criteria. Baseline circulating sclerostin, dickkopf (DKK)-1, secreted frizzled-related protein (SFRP)-1 and Wnt inhibitory factor (WIF)-1 levels were assessed by ELISA.

      Results

      Baseline systemic SFRP-1 and WIF-1 levels were significantly higher in patients with cardiovascular events (n = 70) when compared to healthy controls (n = 157) while DKK-1 and sclerostin levels were similar in both groups. Logistic regression analysis revealed WIF-1 as a significant predictor of future cardiovascular events.

      Conclusions

      Our data suggest that increased SFRP-1 and WIF-1 levels precede the development of symptomatic atherosclerotic disease. Assessment of systemic WIF-1 levels, which turned out to be independently associated with CVD, might help to early identify patients at intermediate cardiovascular risk.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Clevers H.
        Wnt/beta-catenin signaling in development and disease.
        Cell. 2006; 127: 469-480
        • Logan C.Y.
        • Nusse R.
        The wnt signaling pathway in development and disease.
        Annu. Rev. Cell Dev. Biol. 2004; 20: 781-810
        • Bhatt P.M.
        • Malgor R.
        Wnt5a: a player in the pathogenesis of atherosclerosis and other inflammatory disorders.
        Atherosclerosis. 2014; 237: 155-162
        • Miller J.R.
        The wnts.
        Genome biology. 2002; 3 (REVIEWS3001. Epub 2001 Dec 28)
        • Angers S.
        • Moon R.T.
        Proximal events in wnt signal transduction.
        Nat. Rev. Mol. Cell Biol. 2009; 10: 468-477
        • Clevers H.
        • Nusse R.
        Wnt/beta-catenin signaling and disease.
        Cell. 2012; 149: 1192-1205
        • Matthijs Blankesteijn W.
        • Hermans K.C.
        Wnt signaling in atherosclerosis.
        Eur. J. Pharmacol. 2015; 763: 122-130
        • Marinou K.
        • Christodoulides C.
        • Antoniades C.
        • Koutsilieris M.
        Wnt signaling in cardiovascular physiology.
        Trends in endocrinology and metabolism: TEM (Trends Endocrinol. Metab.). 2012; 23: 628-636
        • Shao J.S.
        • Cheng S.L.
        • Pingsterhaus J.M.
        • Charlton-Kachigian N.
        • Loewy A.P.
        • Towler D.A.
        Msx2 promotes cardiovascular calcification by activating paracrine wnt signals.
        The Journal of clinical investigation. 2005; 115: 1210-1220
        • Shao J.S.
        • Aly Z.A.
        • Lai C.F.
        • Cheng S.L.
        • Cai J.
        • Huang E.
        • Behrmann A.
        • Towler D.A.
        Vascular bmp msx2 wnt signaling and oxidative stress in arterial calcification.
        Ann. N. Y. Acad. Sci. 2007; 1117: 40-50
        • Wang X.
        • Xiao Y.
        • Mou Y.
        • Zhao Y.
        • Blankesteijn W.M.
        • Hall J.L.
        A role for the beta-catenin/t-cell factor signaling cascade in vascular remodeling.
        Circ. Res. 2002; 90: 340-347
        • Mani A.
        • Radhakrishnan J.
        • Wang H.
        • Mani A.
        • Mani M.A.
        • Nelson-Williams C.
        • Carew K.S.
        • Mane S.
        • Najmabadi H.
        • Wu D.
        • Lifton R.P.
        Lrp6 mutation in a family with early coronary disease and metabolic risk factors.
        Science. 2007; 315: 1278-1282
        • Christodoulides C.
        • Lagathu C.
        • Sethi J.K.
        • Vidal-Puig A.
        Adipogenesis and wnt signalling.
        Trends in endocrinology and metabolism: TEM (Trends Endocrinol. Metab.). 2009; 20: 16-24
        • Ross S.E.
        • Hemati N.
        • Longo K.A.
        • Bennett C.N.
        • Lucas P.C.
        • Erickson R.L.
        • MacDougald O.A.
        Inhibition of adipogenesis by wnt signaling.
        Science. 2000; 289: 950-953
        • Weivoda M.M.
        • Oursler M.J.
        Developments in sclerostin biology: regulation of gene expression, mechanisms of action, and physiological functions.
        Curr. Osteoporos. Rep. 2014; 12: 107-114
        • Didangelos A.
        • Yin X.
        • Mandal K.
        • Baumert M.
        • Jahangiri M.
        • Mayr M.
        Proteomics characterization of extracellular space components in the human aorta.
        Molecular & cellular proteomics MCP. 2010; 9: 2048-2062
        • Koos R.
        • Brandenburg V.
        • Mahnken A.H.
        • Schneider R.
        • Dohmen G.
        • Autschbach R.
        • Marx N.
        • Kramann R.
        Sclerostin as a potential novel biomarker for aortic valve calcification: an in-vivo and ex-vivo study.
        J. Heart Valve Dis. 2013; 22: 317-325
        • Kuipers A.L.
        • Miljkovic I.
        • Carr J.J.
        • Terry J.G.
        • Nestlerode C.S.
        • Ge Y.
        • Bunker C.H.
        • Patrick A.L.
        • Zmuda J.M.
        Association of circulating sclerostin with vascular calcification in afro-caribbean men.
        Atherosclerosis. 2015; 239: 218-223
        • Ueland T.
        • Otterdal K.
        • Lekva T.
        • Halvorsen B.
        • Gabrielsen A.
        • Sandberg W.J.
        • Paulsson-Berne G.
        • Pedersen T.M.
        • Folkersen L.
        • Gullestad L.
        • Oie E.
        • Hansson G.K.
        • Aukrust P.
        Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1228-1234
        • Lu H.
        • Li X.
        • Mu P.
        • Qian B.
        • Jiang W.
        • Zeng L.
        Dickkopf-1 promotes the differentiation and adipocytokines secretion via canonical wnt signaling pathway in primary cultured human preadipocytes.
        Obes. Res. Clin. Pract. 2016; 10: 454-464
        • Chae W.J.
        • Ehrlich A.K.
        • Chan P.Y.
        • Teixeira A.M.
        • Henegariu O.
        • Hao L.
        • Shin J.H.
        • Park J.H.
        • Tang W.H.
        • Kim S.T.
        • Maher S.E.
        • Goldsmith-Pestana K.
        • Shan P.
        • Hwa J.
        • Lee P.J.
        • Krause D.S.
        • Rothlin C.V.
        • McMahon-Pratt D.
        • Bothwell A.L.
        The wnt antagonist dickkopf-1 promotes pathological type 2 cell-mediated inflammation.
        Immunity. 2016; 44: 246-258
        • Smadja D.M.
        • d'Audigier C.
        • Weiswald L.B.
        • Badoual C.
        • Dangles-Marie V.
        • Mauge L.
        • Evrard S.
        • Laurendeau I.
        • Lallemand F.
        • Germain S.
        • Grelac F.
        • Dizier B.
        • Vidaud M.
        • Bieche I.
        • Gaussem P.
        The wnt antagonist dickkopf-1 increases endothelial progenitor cell angiogenic potential.
        Arterioscler. Thromb. Vasc. Biol. 2010; 30: 2544-2552
        • Barandon L.
        • Casassus F.
        • Leroux L.
        • Moreau C.
        • Allieres C.
        • Lamaziere J.M.
        • Dufourcq P.
        • Couffinhal T.
        • Duplaa C.
        Secreted frizzled-related protein-1 improves postinfarction scar formation through a modulation of inflammatory response.
        Arterioscler. Thromb. Vasc. Biol. 2011; 31: e80-87
        • WHO
        Fact Sheet No 310; the Top 10 Causes of Death.
        World Health Organization, 2017
        • Iglseder B.
        • Mackevics V.
        • Stadlmayer A.
        • Tasch G.
        • Ladurner G.
        • Paulweber B.
        Plasma adiponectin levels and sonographic phenotypes of subclinical carotid artery atherosclerosis: data from the saphir study.
        Stroke. 2005; 36: 2577-2582
        • Kaser S.
        • Sandhofer A.
        • Foger B.
        • Ebenbichler C.F.
        • Igelseder B.
        • Malaimare L.
        • Paulweber B.
        • Patsch J.R.
        Influence of obesity and insulin sensitivity on phospholipid transfer protein activity.
        Diabetologia. 2001; 44: 1111-1117
        • Geisel M.H.
        • Coassin S.
        • Hessler N.
        • Bauer M.
        • Eisele L.
        • Erbel R.
        • Haun M.
        • Hennig F.
        • Moskau-Hartmann S.
        • Hoffmann B.
        • Jockel K.H.
        • Kedenko L.
        • Kiechl S.
        • Kollerits B.
        • Mahabadi A.A.
        • Moebus S.
        • Nurnberg G.
        • Nurnberg P.
        • Paulweber B.
        • Vens M.
        • Willeit J.
        • Willeit K.
        • Klockgether T.
        • Ziegler A.
        • Scherag A.
        • Kronenberg F.
        Update of the effect estimates for common variants associated with carotid intima media thickness within four independent samples: the bonn imt family study, the heinz nixdorf recall study, the saphir study and the bruneck study.
        Atherosclerosis. 2016; 249: 83-87
        • DeLong E.R.
        • DeLong D.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Rudolf J.
        • Lewandrowski K.B.
        Cholesterol, lipoproteins, high-sensitivity c-reactive protein, and other risk factors for atherosclerosis.
        Clin. Lab. Med. 2014; 34 (vii): 113-127
        • Malgor R.
        • Bhatt P.M.
        • Connolly B.A.
        • Jacoby D.L.
        • Feldmann K.J.
        • Silver M.J.
        • Nakazawa M.
        • McCall K.D.
        • Goetz D.J.
        Wnt5a, tlr2 and tlr4 are elevated in advanced human atherosclerotic lesions.
        Inflammation research official journal of the European Histamine Research Society. 2014; 63: 277-285
        • Pashirzad M.
        • Shafiee M.
        • Rahmani F.
        • Behnam-Rassouli R.
        • Hoseinkhani F.
        • Ryzhikov M.
        • Moradi binabaj M.
        • Parizadeh M.R.
        • Avan a
        • Hassanian S.M.
        Role of wnt5a in the pathogenesis of inflammatory diseases.
        J. Cell. Physiol. 2017; 232: 1611-1616
        • Sarzani R.
        • Salvi F.
        • Bordicchia M.
        • Guerra F.
        • Battistoni I.
        • Pagliariccio G.
        • Carbonari L.
        • Dessi-Fulgheri P.
        • Rappelli A.
        Carotid artery atherosclerosis in hypertensive patients with a functional ldl receptor-related protein 6 gene variant.
        Nutrition, metabolism, and cardiovascular diseases NMCD. 2011; 21: 150-156
        • Baarsma H.A.
        • Konigshoff M.
        • Gosens R.
        The wnt signaling pathway from ligand secretion to gene transcription: Molecular mechanisms and pharmacological targets.
        Pharmacol. Therapeut. 2013; 138: 66-83
        • Randrianarisoa E.
        • Rietig R.
        • Jacob S.
        • Blumenstock G.
        • Haering H.U.
        • Rittig K.
        • Balletshofer B.
        Normal values for intima-media thickness of the common carotid artery–an update following a novel risk factor profiling.
        VASA. Zeitschrift fur Gefasskrankheiten. 2015; 44: 444-450
        • Kim K.I.
        • Park K.U.
        • Chun E.J.
        • Choi S.I.
        • Cho Y.S.
        • Youn T.J.
        • Cho G.Y.
        • Chae I.H.
        • Song J.
        • Choi D.J.
        • Kim C.H.
        A novel biomarker of coronary atherosclerosis: serum dkk1 concentration correlates with coronary artery calcification and atherosclerotic plaques.
        J. Kor. Med. Sci. 2011; 26: 1178-1184
        • Wang L.
        • Hu X.B.
        • Zhang W.
        • Wu L.D.
        • Liu Y.S.
        • Hu B.
        • Bi C.L.
        • Chen Y.F.
        • Liu X.X.
        • Ge C.
        • Zhang Y.
        • Zhang M.
        Dickkopf-1 as a novel predictor is associated with risk stratification by grace risk scores for predictive value in patients with acute coronary syndrome: a retrospective research.
        PLoS One. 2013; 8 (e54731)
        • Seifert-Held T.
        • Pekar T.
        • Gattringer T.
        • Simmet N.E.
        • Scharnagl H.
        • Stojakovic T.
        • Fazekas F.
        • Storch M.K.
        Circulating dickkopf-1 in acute ischemic stroke and clinically stable cerebrovascular disease.
        Atherosclerosis. 2011; 218: 233-237
        • Morales-Santana S.
        • Garcia-Fontana B.
        • Garcia-Martin A.
        • Rozas-Moreno P.
        • Garcia-Salcedo J.A.
        • Reyes-Garcia R.
        • Munoz-Torres M.
        Atherosclerotic disease in type 2 diabetes is associated with an increase in sclerostin levels.
        Diabetes Care. 2013; 36: 1667-1674
        • Gaudio A.
        • Privitera F.
        • Pulvirenti I.
        • Canzonieri E.
        • Rapisarda R.
        • Fiore C.E.
        The relationship between inhibitors of the wnt signalling pathway (sclerostin and dickkopf-1) and carotid intima-media thickness in postmenopausal women with type 2 diabetes mellitus.
        Diabetes Vasc. Dis. Res. 2014; 11: 48-52
        • Tsaousi A.
        • Williams H.
        • Lyon C.A.
        • Taylor V.
        • Swain A.
        • Johnson J.L.
        • George S.J.
        Wnt4/beta-catenin signaling induces vsmc proliferation and is associated with intimal thickening.
        Circ. Res. 2011; 108: 427-436
        • Ezan J.
        • Leroux L.
        • Barandon L.
        • Dufourcq P.
        • Jaspard B.
        • Moreau C.
        • Allieres C.
        • Daret D.
        • Couffinhal T.
        • Duplaa C.
        Frza/sfrp-1, a secreted antagonist of the wnt-frizzled pathway, controls vascular cell proliferation in vitro and in vivo.
        Cardiovasc. Res. 2004; 63: 731-738