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NDT Advance Access originally published online on March 30, 2006
Nephrology Dialysis Transplantation 2006 21(9):2672-2674; doi:10.1093/ndt/gfl143
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Letter

The pleiotropic effect of statins in haemodialysis patients is not the consequence of an inhibition of LDL oxidation by myeloperoxidase

Email: pvantwer{at}ulb.ac.be

Sir,

For at least 20 years, myeloperoxidase (MPO) has been studied as a marker of oxidative stress during haemodialysis (HD) [1]. Free MPO concentration increases during HD, which is associated with an increased risk of coronary artery disease [2,3]. In a recent article, statins demonstrated their ability to downregulate the MPO gene expression in human macrophages, which could explain their pleiotropic protection against coronary artery disease [4]. Previous studies also demonstrated that atorvastatin therapy (12 weeks in human) decreased the markers of MPO oxidation [5], while fluvastatin reduced the chlorinating activity of MPO in a rat model [6]. These peculiar results led some authors to investigate the effects of a statin treatment on the MPO activity in HD patients. They showed that the drugs significantly decreased markers of MPO activity, both in diabetic and non-diabetic HD subjects [7].

In our laboratories, we are particularly concerned about the key role of circulating MPO in the development of atherosclerosis. One of the most deleterious mechanisms provided by MPO is probably the oxidative modification of low-density lipoproteins (LDL); MPO binds to LDL [8] and predominantly oxidizes apolipoprotein B-100 [9]. An ELISA test that specifically quantifies the MPO-modified LDL (Mox-LDL) was used to assess the production of Mox-LDL [10,11]. First, we studied the inhibition of the LDL oxidation in the presence of several statin concentrations. Second, we investigated the possible interaction of statins with MPO, using a model based on the accumulation of compound II as previously described [12]. Figure 1 shows that simvastatine and lovastatine, at therapeutic concentrations, were unable to inhibit LDL oxidation. Indeed, simvastatine significantly inhibited LDL oxidation at concentrations over 300 nM. Furthermore, we did not observe any accumulation of the compound II, which indicates the absence of interference of statins with the synthesis of hypochlorous acid.


Figure 1
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  		Fig. 1. Mox-LDL concentrations (in %) in the presence of increasing amounts of lovastatine (lovastat) and simvastatine (simvastat). Native LDL has to be considered equal to 0%, Mox-LDL equal to 100% and catalase (400 U/ml), and the absence of hydrogen peroxide or the absence of MPO as negative controls. Statistics: ANOVA, *P<0.05 vs LDLox, Dunnett's post hoc test, results are the mean±SD of four independent measurements.

 
Our results suggest that LDL binds to MPO and that their presence close to the catalytic site of the enzyme decreases the inhibiting effect of large molecules such as statins [11]. Although fluvastatin undoubtedly scavenges HOCl [6], probably as a consequence of a double bound in its structure, it has no significant inhibiting effect on LDL oxidation by MPO. Our findings suggest that statins do not decrease the risk of coronary artery disease by inhibition of LDL oxidation by MPO, in contrast with the other effects of statins such as the downregulation of MPO gene expression [4], the decrease of oxidation markers [5] and the decrease of markers of MPO activity in HD patients [7]. It could be of great interest to compare these results with the levels of free MPO and Mox-LDL in HD patients treated or not by statins.

P. Van Antwerpen1, K. Zouaoui Boudjeltia2, M. Vaes2, S. Babar2, P. Madhoun3, N. Moguilevsky4, M. Vanhaeverbeek2, J. Néve1 and J. Ducobu5

1 Laboratory of Pharmaceutical Chemistry, Université Libre de Bruxelles Brussels2 Laboratory of Internal Medicine CHU Vesale Université Libre de Bruxelles Montigny-le-Tilleul3 Department of Nephrology and Haemodialysis CHU Vesale Montigny-le-Tilleul4 Technology Transfert Office FUNDP, Namur5 Department of Internal Medicine CHU Tivoli La Louviére, Belgium

References

  1. Borawski J. Myeloperoxidase as a marker of hemodialysis biocompatibility and oxidative stress: the underestimated modifying effects of heparin. Am J kidney dis 2006; 47: 37–41[CrossRef][Web of Science][Medline]
  2. Wu CC, Chen, JS, Wu WM et al. Myeloperoxidase serves as a marker of oxidative stress during single haemodialysis session using two different biocompatible membranes. Nephrol Dial Transplat 2005; 20: 1134–1139
  3. Zhang R, Brennan ML, Fu X et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001; 286: 2136–2142[Abstract/Free Full Text]
  4. Kumar AP, Reynolds WF. Statins downregulate myeloperoxidase gene expression in macrophages. Biochem Biophys Res Comm 2005; 331: 442–451[CrossRef][Web of Science][Medline]
  5. Shishehbor MH, Brennan ML, Ronnier J et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003; 108: 426–431[Abstract/Free Full Text]
  6. Tiefenbacher CP, Kapitza J, Dietz V et al. Reduction of myocardial infarct size by fluvastatin. Am J Pysiol Heart Circ Physiol 2003; 285: H59–H64
  7. Stenvinkel P, Rodriguez-Ayala E, Massy ZA et al. Statin treatment and diabetes affect myeloperoxidase activity in maintenance hemodialysis patients. Clin J Am Soc Nephrol 2006; in press
  8. Carr AC, Myzak MC, Stocker R et al. Myeloperoxidase binds to low-density lipoprotein: potential implications for atherosclerosis. FEBS Letters 2000; 487: 176–180[CrossRef][Web of Science][Medline]
  9. Hazell JL, Van den Berg JJM, Stocker R. Oxidation of low density lipoprotein by hypochlorite causes aggregation that is mediated by modification of lysine residues rather than lipid oxidation. Biochem J 1994; 304: 297–304
  10. Moguilevsky N, Zouaoui Boudjeltia K, Babar S et al. Monoclonal antibodies against LDL progressively oxidized by myeloperoxidase react with ApoB-100 protein moiety and human atherosclerotic lesions. Biochem Biophys Res Comm 2004; 323: 1223–1228[Medline]
  11. Van Antwerpen P, Zouaoui Boudjeltia K, Babar S et al. Thiol-containing molecules interact with the MPO/H2O2/Chloride system to inhibit LDL oxidation. Biochem Biophys Res Comm 2005; 337: 82–88[CrossRef][Medline]
  12. Nève J, Parij N, Moguilevsky N. Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs investigated with a human recombinant enzyme. Eur J of Pharm 2001; 417: 37–43

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This Article
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