Modification of HDL3 by mild oxidative stress increases ATP-binding cassette transporter 1-mediated cholesterol efflux.
OBJECTIVE
Elevated levels of high-density lipoprotein (HDL) cholesterol are inversely related to the risk of cardiovascular disease. The anti-atherosclerotic function of HDL is mainly ascribed to its role in reverse cholesterol transport, and requires the integrity of HDL structure. Experimental evidence suggests that the ability of HDL to promote removal of excess cholesterol from peripheral cells is impaired upon oxidation. On the other hand, tyrosylation of HDL enhances its protective function, suggesting that not all forms of modified lipoprotein may be atherogenic. In the present study we investigated the effect of a mild oxidation of HDL(3) on its function as cholesterol acceptor.


RESULTS
A mild oxidative stress (induced by 15 min exposure of HDL(3) to 1 microM Cu(++) or to 15-lipoxygenase) caused the formation of pre-beta-migrating particles. Compared to native lipoprotein, mildly modified HDL(3) induced a significant ATP-binding cassette transporter 1 (ABCA1)-mediated increase of cholesterol and phospholipids efflux from J774 macrophages. This effect was abolished by an inhibitor of ABCA1-mediated lipid efflux (glyburide) and was absent in Tangier fibroblasts.


CONCLUSIONS
A mild oxidative modification of HDL(3) may improve its function as cholesterol acceptor, increasing ABCA1-mediated lipid efflux from macrophages, a process that may reduce foam cell formation.
Pirillo
Angela
A
Department of Pharmacological Sciences, Via Balzaretti, 9, 20133 Milano, Italy. angela.pirillo@unimi.it
Uboldi
Patrizia
P
Pappalardo
Gianluca
G
Kuhn
Hartmut
H
Catapano
Alberico L
AL
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D053440:Lipoproteins, HDL3 / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D053440:Lipoproteins, HDL3; D010743:Phospholipids; D003300:Copper; D002784:Cholesterol; D001093:Arachidonate 15-Lipoxygenase; D005905:Glyburide