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Decreased serum levels of thioredoxin in patients with coronary artery disease plus hyperhomocysteinemia is strongly associated with the disease severity

  • Author Footnotes
    1 These authors contributed equally to this work.
    Yunfei Wu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    College of Life Sciences, Graduate University of Chinese Academy of Sciences, Yuquan Road 19(A), 100049 Beijing, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Lijuan Yang
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Department of Endocrinology, Chinese PLA General Hospital, 100853 Beijing, China
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  • Liangwei Zhong
    Correspondence
    Corresponding author. Tel.: +86 10 88256266; fax: +86 10 88256266.
    Affiliations
    College of Life Sciences, Graduate University of Chinese Academy of Sciences, Yuquan Road 19(A), 100049 Beijing, China
    Search for articles by this author
  • Author Footnotes
    1 These authors contributed equally to this work.

      Abstract

      Objective

      Elevation of homocysteine and thioredoxin (Trx) levels was found in some patients with coronary artery diseases (CAD). However, their correlations with CAD were not clear. Dysfunction of thioredoxin/thioredoxin reductase (TrxR) may cause oxidative stress that is common to CAD. We seek to determine the association among homocysteine, Trx/TrxR and CAD.

      Methods

      Serum samples were collected from 150 CAD patients under statin treatment and 122 non-CAD controls. Risk factors for atherosclerosis including homocysteine, lipids and glucose levels were analyzed. Trx/TrxR activities and protein levels were determined using super-insulin assay and Western blot, respectively. One-way ANOVA, Tukey's post hoc test and Spearman's rank correlation coefficient were used for statistical analysis. CAD severity was evaluated by angiographic Gensini score.

      Results

      Compared with non-CAD group, CAD group had significantly increased TrxR activity (P < 0.05) and homocysteine levels (P < 0.01), but not Trx activity. After further dividing CAD group using homocysteine below 15 μM as reference, Trx activity decreased significantly in CAD group with high homocysteine, and was inversely associated with homocysteine levels (r = −0.199, P < 0.05) that was, however, weakly positively associated with TrxR activity. Neither lipids nor glucose significantly affected Trx/TrxR activity. Association of CAD severity with low Trx plus high homocysteine was strong (r = −0.458, P < 0.001), but with high homocysteine alone was rather weak (r = 0.125, P = 0.225).

      Conclusion

      In CAD patients, high homocysteine levels may cause low Trx activity, which is closely correlated to the extent and severity of CAD.

      Keywords

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      References

        • Nygard O.
        • Nordrehaug J.E.
        • Refsum H.
        • et al.
        Plasma homocysteine levels and mortality in patients with coronary artery disease.
        N Engl J Med. 1997; 337: 230-236
        • Zou C.G.
        • Banerjee R.
        Homocysteine and redox signaling.
        Antioxid Redox Signal. 2005; 7: 547-559
        • Tyagi N.
        • Sedoris K.C.
        • Steed M.
        • et al.
        Mechanisms of homocysteine-induced oxidative stress.
        Am J Physiol Heart Circ Physiol. 2005; 289: H2649-H2656
        • Dai J.
        • Wang X.
        • Feng J.
        • et al.
        Regulatory role of thioredoxin in homocysteine-induced monocyte chemoattractant protein-1 secretion in monocytes/macrophages.
        FEBS Lett. 2008; 582: 3893-3898
        • Cha M.K.
        • Kim I.H.
        Thioredoxin-linked peroxidase from human red blood cell: evidence for the existence of thioredoxin and thioredoxin reductase in human red blood cell.
        Biochem Biophys Res Commun. 1995; 217: 900-907
        • Kim H.Y.
        • Kim J.R.
        Thioredoxin as a reducing agent for mammalian methionine sulfoxide reductases B lacking resolving cysteine.
        Biochem Biophys Res Commun. 2008; 371: 490-494
        • Cheng Z.
        • Arscott L.D.
        • Ballou D.P.
        • et al.
        The relationship of the redox potentials of thioredoxin and thioredoxin reductase from Drosophila melanogaster to the enzymatic mechanism: reduced thioredoxin is the reductant of glutathione in Drosophila.
        Biochemistry. 2007; 46: 7875-7885
        • Holmgren A.
        Thioredoxin.
        Annu Biochem Rev. 1985; 54: 237-271
        • Song J.J.
        • Lee Y.J.
        Differential role of glutaredoxin and thioredoxin in metabolic oxidative stress-induced activation of apoptosis signal-regulating kinase 1.
        Biochem J. 2003; 373: 845-853
        • Holmgren A.
        • Johansson C.
        • Berndt C.
        • et al.
        Thiol redox control via thioredoxin and glutaredoxin systems.
        Biochem Soc Trans. 2005; 33: 1375-1377
        • Zhong L.
        • Holmgren A.
        Mammalian thioredoxin reductases as hydroperoxide reductases.
        Methods Enzymol. 2002; 347: 236-243
        • Bjornstedt M.
        • Hamberg M.
        • Kumar S.
        • et al.
        Human thioredoxin reductase directly reduces lipid hydroperoxides by NADPH and selenocystine strongly stimulates the reaction via catalytically generated selenols.
        J Biol Chem. 1995; 270: 11761-11764
        • May J.M.
        • Mendiratta S.
        • Hill K.E.
        • et al.
        Reduction of dehydroascorbate to ascorbate by the selenoenzyme thioredoxin reductase.
        J Biol Chem. 1997; 272: 22607-22610
        • Benhar M.
        • Forrester M.T.
        • Stamler J.S.
        Protein denitrosylation: enzymatic mechanisms and cellular functions.
        Nat Rev Mol Cell Biol. 2009; 10: 721-732
        • Arner E.S.
        • Holmgren A.
        Physiological functions of thioredoxin and thioredoxin reductase.
        Eur J Biochem. 2000; 267: 6102-6109
        • Hagg D.
        • Englund M.C.
        • Jernas M.
        • et al.
        Oxidized LDL induces a coordinated up-regulation of the glutathione and thioredoxin systems in human macrophages.
        Atherosclerosis. 2006; 185: 282-289
        • Sahaf B.
        • Rosen A.
        Secretion of 10-kDa and 12-kDa thioredoxin species from blood monocytes and transformed leukocytes.
        Antioxid Redox Signal. 2000; 2: 717-726
        • Miyamoto S.
        • Kawano H.
        • Hokamaki J.
        • et al.
        Increased plasma levels of thioredoxin in patients with glucose intolerance.
        Intern Med. 2005; 44: 1127-1132
        • Soejima H.
        • Suefuji H.
        • Miyamoto S.
        • et al.
        Increased plasma thioredoxin in patients with acute myocardial infarction.
        Clin Cardiol. 2003; 26: 583-587
        • Nishihira K.
        • Yamashita A.
        • Imamura T.
        • et al.
        Thioredoxin in coronary culprit lesions: possible relationship to oxidative stress and intraplaque hemorrhage.
        Atherosclerosis. 2008; 201: 360-367
        • Malinow M.R.
        Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review.
        Clin Chem. 1995; 41: 173-176
        • Gensini G.G.
        A more meaningful scoring system for determining the severity of coronary heart disease.
        Am J Cardiol. 1983; 51: 606
        • Das K.C.
        • Das C.K.
        • Thioredoxin
        a singlet oxygen quencher and hydroxyl radical scavenger: redox independent functions.
        Biochem Biophys Res Commun. 2000; 277: 443-447
        • Hashimoto S.
        • Matsumoto K.
        • Gon Y.
        • et al.
        Thioredoxin negatively regulates p38 MAP kinase activation and IL-6 production by tumor necrosis factor-alpha.
        Biochem Biophys Res Commun. 1999; 258: 443-447
        • Weichsel A.
        • Gasdaska J.R.
        • Powis G.
        • et al.
        Crystal structures of reduced, oxidized, and mutated human thioredoxins: evidence for a regulatory homodimer.
        Structure. 1996; 4: 735-751
        • Lubos E
        • Loscalzo J.
        • Handy D.E.
        Homocysteine and glutathione peroxidase-1.
        Antioxid Redox Signal. 2007; 9: 1923-1940
        • Moon S.
        • Fernando M.R.
        • Lou M.F.
        Induction of thioltransferase and thioredoxin/thioredoxin reductase systems in cultured porcine lenses under oxidative stress.
        Invest Ophthalmol Vis Sci. 2005; 46: 3783-3789
        • Lim H.W.
        • Hong S.
        • Jin W.
        • et al.
        Up-regulation of defense enzymes is responsible for low reactive oxygen species in malignant prostate cancer cells.
        Exp Mol Med. 2005; 37: 497-506
        • Lu J.
        • Zhong L.
        • Lonn M.E.
        • et al.
        Penultimate selenocysteine residue replaced by cysteine in thioredoxin reductase from selenium-deficient rat liver.
        FASEB J. 2009; 23: 2394-2402
        • Baber U.
        • Toto R.D.
        • de Lemos J.A.
        Statins and cardiovascular risk reduction in patients with chronic kidney disease and end-stage renal failure.
        Am Heart J. 2007; 153: 471-477