Myeloperoxidase-derived chlorinating species induce protein carbamylation through decomposition of thiocyanate and urea: Novel pathways generating dysfunctional high-density lipoprotein

Michael Holzer, Klaus Zangger, Dalia El-Gamal, Veronika Binder, Sanja Curcic, Viktoria Konya, Rufina Schuligoi, Akos Heinemann, Gunther Marsche

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Abstract

Aims: Protein carbamylation through cyanate is considered as playing a causal role in promoting cardiovascular disease. We recently observed that the phagocyte protein myeloperoxidase (MPO) specifically induces high-density lipoprotein (HDL) carbamylation, rather than chlorination, in human atherosclerotic lesions, raising the possibility that MPO-derived chlorinating species are involved in cyanate formation. Results: Here, we show that MPO-derived chlorinating species rapidly decompose the plasma components thiocyanate (SCN) and urea, thereby promoting (lipo)protein carbamylation. Strikingly, the presence of physiologic concentrations of SCN completely prevented MPO-induced 3-chlorotyrosine formation in HDL. SCN scavenged a 2.5-fold molar excess of hypochlorous acid, promoting HDL carbamylation, but not chlorination. Cyanate significantly impaired (i) HDL's ability to activate lecithin-cholesterol acyltransferase; (ii) the activity of paraoxonase, a major HDL-associated anti-inflammatory enzyme; and (iii) the antioxidative activity of HDL. Innovation: Here, we report that MPO-derived chlorinating species preferentially induce protein carbamylation-rather than chlorination-in the presence of physiologically relevant SCN concentrations. The carbamylation of HDL results in the loss of its anti-inflammatory and antioxidative activities. Conclusion: MPO-mediated decomposition of SCN and/or urea might be a relevant mechanism for generating dysfunctional HDL in human disease. Antioxid. Redox Signal. 00, 000-000.

Original languageEnglish (US)
Pages (from-to)1043-1052
Number of pages10
JournalAntioxidants and Redox Signaling
Volume17
Issue number8
DOIs
StatePublished - Oct 15 2012

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ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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