The myeloperoxidase product hypochlorous acid generates irreversible high-density lipoprotein receptor inhibitors

Veronika Binder, Senka Ljubojevic, Johannes Haybaeck, Michael Holzer, Dalia El-Gamal, Rudolf Schicho, Burkert Pieske, Akos Heinemann, Gunther Marsche

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

OBJECTIVE - : Elevated levels of advanced oxidation protein products have been described in several chronic inflammatory diseases, like chronic renal insufficiency, rheumatoid arthritis, and atherosclerosis. Recent findings revealed that advanced oxidation protein products are inhibitors of the major high-density lipoprotein receptor, scavenger receptor class B, type 1 (SR-BI). Here, we investigated which oxidation-induced structural alterations convert plasma albumin into a high-density lipoprotein-receptor inhibitor. APPROACH AND RESULTS - : Exposure of albumin to the physiological oxidant, hypochlorous acid, generated high-affinity SR-BI ligands. Protection of albumin-lysine residues before exposure to hypochlorous acid as well as regeneration of N-chloramines after oxidation of albumin completely prevented binding of oxidized albumin to SR-BI, indicating that modification of albumin-lysine residues is required to generate SR-BI ligands. Of particular interest, N-chloramines within oxidized albumin promoted irreversible binding to SR-BI, resulting in permanent receptor blockade. We observed that the SR-BI inhibitory activity of albumin isolated from chronic kidney disease patients correlated with the content of the myeloperoxidase-specific oxidation product 3-chlorotyrosine and was associated with alterations in the composition of high-density lipoprotein. CONCLUSIONS - : Given that several potential atheroprotective activities of high-density lipoprotein are mediated by SR-BI, the present results raise the possibility that oxidized plasma albumin, through permanent SR-BI blockade, contributes to the pathophysiology of cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)1020-1027
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number5
DOIs
StatePublished - May 1 2013

Keywords

  • advanced oxidation protein products
  • atherosclerosis
  • end-stage renal disease
  • high-density lipoprotein- metabolism
  • high-density lipoprotein-composition
  • myeloperoxidase
  • scavenger receptor class B, type 1

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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