Oxidative modification of lipoprotein(a) and the effect of beta-carotene.
Lipoprotein (a) [Lp(a)] particles isolated and purified from human plasma were found to be oxidatively modified when incubated in vitro with human mononuclear cells or Cu2+. This modification, which involved lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS), caused marked changes in the structure and biological properties of Lp(a). Relative to native Lp(a), oxidized particles showed decreases of free amino groups, protein fragmentation, increased negative charge, and high aggregation ability. They were taken up and degraded readily by macrophages in vitro, inducing cholesteryl ester accumulation. When apolipoprotein (a) [apo(a)] was clipped off by exposure to dithiothreitol (DTT), the remaining particle was degraded by macrophages at a significantly lower rate. This observation implies that oxidative modification of apo(a) may have an influence on Lp(a) recognition by scavenger receptors of macrophages. Under the same experimental conditions, low-density lipoprotein (LDL) concentrations equal to those of Lp(a) showed a lower susceptibility to oxidation. This was probably due to higher vitamin E (30% more) and beta-carotene (40% more) content compared with Lp(a), when expressed as a function of cholesterol concentration and measured in the same subject. The addition of beta-carotene to Lp(a) in vitro partially protected Lp(a) against oxidation and aggregation. As a result, uptake of oxidized Lp(a) by macrophages decreased markedly. We conclude that Lp(a) particles are prone to oxidation and that the increased risk of coronary artery disease associated with elevated Lp(a) levels may be related in part to their oxidative modification and uptake by macrophages, resulting in the formation of macrophage-derived foam cells.
Naruszewicz
M
M
Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Quebec, Canada.
Selinger
E
E
Davignon
J
J
D000328:Adult; D000818:Animals; D002338:Carotenoids / Q000494:pharmacology*; D002784:Cholesterol / Q000032:analysis; D003300:Copper / Q000494:pharmacology; D004587:Electrophoresis, Agar Gel; D006801:Humans; D007457:Iodine Radioisotopes; D017270:Lipoprotein(a) / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010529:Peritoneal Cavity / Q000166:cytology; D019207:beta Carotene
D007457:Iodine Radioisotopes; D017270:Lipoprotein(a); D019207:beta Carotene; D002338:Carotenoids; D003300:Copper; D002784:Cholesterol