Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins

comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl)

Katrina A. Hadfield, David I. Pattison, Bronwyn E. Brown, Liming Hou, Kerry-Anne Rye, Michael J. Davies, Clare L. Hawkins*

*Corresponding author for this work

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Oxidative modification of HDLs (high-density lipoproteins) by MPO (myeloperoxidase) compromises its anti-atherogenic properties, which may contribute to the development of atherosclerosis. Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined. In the present study, we characterize the structural and functional modifications of lipid-free apoA-I and rHDL (reconstituted discoidal HDL) containing apoA-I complexed with phospholipid, induced by HOSCN and its decomposition product, OCN- (cyanate). Treatment of apoA-I with HOSCN resulted in the oxidation of tryptophan residues, whereas OCN- induced carbamylation of lysine residues to yield homocitrulline. Tryptophan residues were more readily oxidized on apoA-I contained in rHDLs. Exposure of lipid-free apoA-I to HOSCN and OCN- significantly reduced the extent of cholesterol efflux from cholesterol-loaded macrophages when compared with unmodified apoA-I. In contrast, HOSCN did not affect the anti-inflammatory properties of rHDL. The ability of HOSCN to impair apoA-I-mediated cholesterol efflux may contribute to the development of atherosclerosis, particularly in smokers who have high plasma levels of SCN- (thiocyanate).

Original languageEnglish
Pages (from-to)531-542
Number of pages12
JournalBiochemical Journal
Volume449
Issue number2
DOIs
Publication statusPublished - 15 Jan 2013
Externally publishedYes

Keywords

  • Atherosclerosis
  • Cholesterol efflux
  • High-density lipoprotein
  • Hypothiocyanous acid
  • Myeloperoxidase
  • Protein oxidation

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