title: Hypochlorite-modified high density lipoprotein, a high affinity ligand to scavenger receptor class B, type I, impairs high density lipoprotein-dependent selective lipid uptake and reverse cholesterol transport.
abstract: Hypochlorous acid/hypochlorite (HOCl/OCl(-)), a potent oxidant generated in vivo by the myeloperoxidase-H(2)O(2)-chloride system of activated phagocytes, alters the physiological properties of high density lipoprotein (HDL) by generating a proatherogenic lipoprotein particle. On endothelial cells lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) and scavenger receptor class B, type I (SR-BI), act in concert by mediating the holoparticle of and selective cholesteryl ester uptake from HOCl-HDL. We therefore investigated the ligand specificity of HOCl-HDL to SR-BI-overexpressing Chinese hamster ovary cells. Binding of HOCl-HDL was saturable, and the degree of HOCl modification was the determining factor for increased binding affinity to SR-BI. Competition experiments further confirmed that HOCl-HDL binds with increased affinity to the same or overlapping domain(s) of SR-BI as does native HDL. Furthermore, SR-BI-mediated selective HDL-cholesteryl ester association as well as time- and concentration-dependent cholesterol efflux from SR-BI overexpressing Chinese hamster ovary cells were, depending on the degree of HOCl modification of HDL, markedly impaired. The most significant findings of this study were that the presence of very low concentrations of HOCl-HDL severely impaired SR-BI-mediated bidirectional cholesterol flux mediated by native HDL. The colocalization of immunoreactive HOCl-modified epitopes with apolipoprotein A-I along with deposits of lipids in serial sections of human atheroma shown here indicates that the myeloperoxidase-H(2)O(2)-halide system contributes to oxidative damage of HDL in vivo.
authors.affiliation: Institute of Medical Biochemistry and Molecular Biology, Karl-Franzens University Graz, Austria.
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.forename: Astrid
authors.initials: A
authors.lastname: Hammer
authors.forename: Olga
authors.initials: O
authors.lastname: Oskolkova
authors.forename: Karen F
authors.initials: KF
authors.lastname: Kozarsky
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sattler
authors.forename: Ernst
authors.initials: E
authors.lastname: Malle
mesh_terms: D000596:Amino Acids / Q000032:analysis; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D016466:CHO Cells; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008075:Lipoproteins, HDL / Q000097:blood / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins; D018613:Microscopy, Confocal; D016877:Oxidants / Q000494:pharmacology; D010743:Phospholipids / Q000302:isolation & purification / Q000378:metabolism*; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein / Q000378:metabolism*; D051116:Receptors, Scavenger; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D051122:Scavenger Receptors, Class B; D051127:Scavenger Receptors, Class E; D014162:Transfection
chemical_list: D000596:Amino Acids; D018955:CD36 Antigens; D005230:Fatty Acids, Nonesterified; D008024:Ligands; D008075:Lipoproteins, HDL; D008565:Membrane Proteins; D016877:Oxidants; D010743:Phospholipids; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D011994:Recombinant Proteins; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D051127:Scavenger Receptors, Class E; D006997:Hypochlorous Acid; D002784:Cholesterol