Mild oxidation promotes and advanced oxidation impairs remodeling of human high-density lipoprotein in vitro |
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Authors: | Gao Xuan Jayaraman Shobini Gursky Olga |
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Affiliation: | Department of Physiology and Biophysics, W329, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA |
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Abstract: | High-density lipoproteins (HDLs) prevent atherosclerosis by removing cholesterol from macrophages and by exerting antioxidant and anti-inflammatory effects. Oxidation is thought to impair HDL functions, yet certain oxidative modifications may be advantageous; thus, mild oxidation reportedly enhances cell cholesterol uptake by HDL whereas extensive oxidation impairs it. To elucidate the underlying energetic and structural basis, we analyzed the effects of copper and hypochlorite (which preferentially oxidize lipids and proteins, respectively) on thermal stability of plasma spherical HDL. Circular dichroism, light scattering, calorimetry, gel electrophoresis, and electron microscopy showed that mild oxidation destabilizes HDL and accelerates protein dissociation and lipoprotein fusion, while extensive oxidation inhibits these reactions; this inhibition correlates with massive protein cross-linking and with lipolysis. We propose that mild oxidation lowers kinetic barriers for HDL remodeling due to diminished apolipoprotein affinity for lipids resulting from oxidation of methionine and aromatic residues in apolipoproteins A-I and A-II followed by protein cross-linking into dimers and/or trimers. In contrast, advanced oxidation inhibits protein dissociation and HDL fusion due to lipid redistribution from core to surface upon lipolysis and to massive protein cross-linking. Our results help reconcile the apparent controversy in the studies of oxidized HDL and suggest that mild oxidation may benefit HDL functions. |
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Keywords: | HDL, high-density lipoprotein nHDL, native (nonoxidized) HDL mHDL, mildly oxidized HDL oxHDL, extensively oxidized HDL LDL, low-density lipoprotein apo, apolipoprotein PC, phosphatidylcholine MetO, methionine sulfoxide (S 0" alt=" double bond length as m-dash" src=" http://cdn.els-cdn.com/sd/entities/dbnd" class=" glyphImg" >O) CD, circular dichroism DSC, differential scanning calorimetry T jump, temperature jump SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis EDTA, ethylenediaminetetraacetic acid |
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