title: The myeloperoxidase product hypochlorous acid generates irreversible high-density lipoprotein receptor inhibitors.
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.
  
  
  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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4 8010 Graz, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Binder
authors.forename: Senka
authors.initials: S
authors.lastname: Ljubojevic
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Michael
authors.initials: M
authors.lastname: Holzer
authors.forename: Dalia
authors.initials: D
authors.lastname: El-Gamal
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schicho
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D016466:CHO Cells; D002318:Cardiovascular Diseases / Q000209:etiology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009195:Peroxidase / Q000378:metabolism; D018110:Receptors, Lipoprotein / Q000037:antagonists & inhibitors*; D012709:Serum Albumin / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D008075:Lipoproteins, HDL; D018110:Receptors, Lipoprotein; D012709:Serum Albumin; C031616:high density lipoprotein receptors; D006997:Hypochlorous Acid; D009195:Peroxidase