Increased cholesterol deposition, expression of scavenger receptors, and response to chemotactic factors in Abca1-deficient macrophages.
OBJECTIVE
Studies in bone marrow transplanted from ATP-binding cassette transporter A1 (ABCA1)-deficient mice into normal mice provides direct evidence that the absence of leukocyte ABCA1 exerts a marked proatherogenic effect independent of changes in plasma lipids, suggesting that ABCA1 plays a key role in the regulation of cholesterol homeostasis and function of macrophages. Therefore, we examined whether the absence of ABCA1 affects the morphology, properties, and functional activities of macrophages that could be related to the development of atherosclerosis.


RESULTS
We conducted a series of experiments in macrophages isolated from Abca1-deficient and wild-type mice and compared several of their properties that are thought to be related to the development of atherosclerosis. Macrophages isolated from Abca1-deficient mice have an increase in cholesterol content, expression of scavenger receptors, and secretion of chemokines, growth factors, and cytokines, resulting in an increased ability to respond to a variety of chemotactic factors.


CONCLUSIONS
Our studies indicate that the absence of ABCA1 leads to significant changes in the morphology, properties, and functional activities of macrophages. These changes, together with the proinflammatory condition present in ABCA1-deficient mice and increased reactivity of macrophages to chemotactic factors, play a key role in the development and progression of atherosclerosis.
Francone
Omar L
OL
Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Groton, CT 06340. omar.l.francone@pfizer.com
Royer
Lori
L
Boucher
Germaine
G
Haghpassand
Mehrdad
M
Freeman
Ann
A
Brees
Dominique
D
Aiello
Robert J
RJ
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D051116:Receptors, Scavenger / Q000235:genetics*; D012772:Shock, Septic / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018925:Chemokines; D008070:Lipopolysaccharides; D051116:Receptors, Scavenger; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol