title: Myeloperoxidase-derived chlorinating species induce protein carbamylation through decomposition of thiocyanate and urea: novel pathways generating dysfunctional high-density lipoprotein.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  MPO-mediated decomposition of SCN and/or urea might be a relevant mechanism for generating dysfunctional HDL in human disease.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Holzer
authors.forename: Klaus
authors.initials: K
authors.lastname: Zangger
authors.forename: Dalia
authors.initials: D
authors.lastname: El-Gamal
authors.forename: Veronika
authors.initials: V
authors.lastname: Binder
authors.forename: Sanja
authors.initials: S
authors.lastname: Curcic
authors.forename: Viktoria
authors.initials: V
authors.lastname: Konya
authors.forename: Rufina
authors.initials: R
authors.lastname: Schuligoi
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D002713:Chlorine / Q000378:metabolism*; D006801:Humans; D006997:Hypochlorous Acid / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000302:isolation & purification / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism*; D013861:Thiocyanates / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D014508:Urea / Q000097:blood / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D008075:Lipoproteins, HDL; D013861:Thiocyanates; D002713:Chlorine; D006997:Hypochlorous Acid; D014508:Urea; D009195:Peroxidase; D008239:Lysine; C031760:thiocyanate