Class B scavenger receptors CD36 and SR-BI are receptors for hypochlorite-modified low density lipoprotein.
The presence of HOCl-modified epitopes inside and outside monocytes/macrophages and the presence of HOCl-modified apolipoprotein B in atherosclerotic lesions has initiated the present study to identify scavenger receptors that bind and internalize HOCl-low density lipoprotein (LDL). The uptake of HOCl-LDL by THP-1 macrophages was not saturable and led to cholesterol/cholesteryl ester accumulation. HOCl-LDL is not aggregated in culture medium, as measured by dynamic light scattering experiments, but internalization of HOCl-LDL could be inhibited in part by cytochalasin D, a microfilament disrupting agent. This indicates that HOCl-LDL is partially internalized by a pathway resembling phagocytosis-like internalization (in part by fluid-phase endocytosis) as measured with [14C]sucrose uptake. In contrast to uptake studies, binding of HOCl-LDL to THP-1 cells at 4 degrees C was specific and saturable, indicating that binding proteins and/or receptors are involved. Competition studies on THP-1 macrophages showed that HOCl-LDL does not compete for the uptake of acetylated LDL (a ligand to scavenger receptor class A) but strongly inhibits the uptake of copper-oxidized LDL (a ligand to CD36 and SR-BI). The binding specificity of HOCl-LDL to class B scavenger receptors could be demonstrated by Chinese hamster ovary cells overexpressing CD36 and SR-BI and specific blocking antibodies. The lipid moiety isolated from the HOCl-LDL particle did not compete for cell association of labeled HOCl-LDL to CD36 or SR-BI, suggesting that the protein moiety of HOCl-LDL is responsible for receptor recognition. Experiments with Chinese hamster ovary cells overexpressing scavenger receptor class A, type I, confirmed that LDL modified at physiologically relevant HOCl concentrations is not recognized by this receptor.
Marsche
Gunther
G
Karl-Franzens University Graz, Institute of Medical Biochemistry and Molecular Biology, Austria.
Zimmermann
Robert
R
Horiuchi
Seikoh
S
Tandon
Narendra N
NN
Sattler
Wolfgang
W
Malle
Ernst
E
D000818:Animals; D001667:Binding, Competitive; D018955:CD36 Antigens / Q000502:physiology*; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D003300:Copper / Q000737:chemistry; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis; D006801:Humans; D006997:Hypochlorous Acid / Q000494:pharmacology*; D007700:Kinetics; D008024:Ligands; D008027:Light; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D010587:Phagocytosis; D011485:Protein Binding; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D012542:Scattering, Radiation; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D013696:Temperature
D018955:CD36 Antigens; D002788:Cholesterol Esters; D008024:Ligands; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D006997:Hypochlorous Acid; D003300:Copper; D002784:Cholesterol