Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages.
Glutaraldehyde treatment of (125)I-labeled low density lipoprotein ((125)I-native-LDL) produced a modified LDL ((125)I-glut-LDL) with a molecular weight of 10 x 10(6) or more. Malondialdehyde treatment of (125)I-native-LDL produced a product ((125)I-MDA-LDL) with a molecular weight not appreciably different from that of the original lipoprotein. However, the electrophoretic mobility of MDA-LDL indicated a more negative charge than native-LDL. (125)I-MDA-LDL was degraded by two processes: a high-affinity saturable process with maximal velocity at 10-15 mug of protein per ml and a slower, nonsaturable process. The degradation of (125)I-MDA-LDL was readily inhibited by increasing concentrations of nonradioactive MDA-LDL but was not inhibited by acetylated LDL or native-LDL even at concentrations as high as 1600 mug of protein per ml. After exposure of native-LDL to blood platelet aggregation and release in vitro, 1.73 +/- 0.19 nmol of malondialdehyde per mg of LDL protein was bound to the platelet-modified-LDL. No detectable malondialdehyde was recovered from native-LDL that had been treated identically except that the platelets were omitted from the reaction mixture. After incubation with glut-LDL, MDA-LDL, or platelet-modified-LDL for 3 days, human monocyte-macrophages showed a dramatic increase in cholesteryl ester content whereas the cholesteryl ester content of cells incubated with the same concentration of native-LDL did not. Based on these experiments we propose that modification of native-LDL may be a prerequisite to the accumulation of cholesteryl esters within the cells of the atherosclerotic reaction. We further hypothesize that one modification of LDL in vivo may result from malondialdehyde which is released from blood platelets or is produced by lipid peroxidation at the site of arterial injury.
D001161:Arteriosclerosis / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism*; D005976:Glutaral / Q000494:pharmacology; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008314:Malonates / Q000494:pharmacology*; D008315:Malondialdehyde / Q000494:pharmacology*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism*; D010974:Platelet Aggregation
D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D008314:Malonates; D008315:Malondialdehyde; D005976:Glutaral