Macrophage ATP-binding cassette transporter A1 overexpression inhibits atherosclerotic lesion progression in low-density lipoprotein receptor knockout mice.
BACKGROUND
ATP-binding cassette transporter A1 (ABCA1) is a key regulator of cellular cholesterol and phospholipid transport. Previously, we have shown that inactivation of macrophage ABCA1 induces atherosclerosis in low-density lipoprotein receptor knockout (LDLr-/-) mice. However, the possibly beneficial effects of specific upregulation of macrophage ABCA1 on atherogenesis are still unknown.


RESULTS
Chimeras that specifically overexpress ABCA1 in macrophages were generated by transplantation of bone marrow from human ABCA1 bacterial artificial chromosome (BAC) transgenic mice into LDLr-/- mice. Peritoneal macrophages isolated from the ABCA1 BAC --> LDLr-/- chimeras exhibited a 60% (P=0.0006) increase in cholesterol efflux to apolipoprotein AI. To induce atherosclerosis, the mice were fed a Western-type diet containing 0.25% cholesterol and 15% fat for 9, 12, and 15 weeks, allowing analysis of effects on initial lesion development as well as advanced lesions. No significant effect of macrophage ABCA1 overexpression was observed on atherosclerotic lesion size after 9 weeks on the Western-type diet (245+/-36x10(3) microm2 in ABCA1 BAC --> LDLr-/- mice versus 210+/-20x10(3) microm2 in controls). However, after 12 weeks, the mean atherosclerotic lesion area in ABCA1 BAC --> LDLr-/- mice remained only 164+/-15x10(3) microm2 (P=0.0008) compared with 513+/-56x10(3) microm2 in controls (3.1-fold lower). Also, after 15 weeks on the diet, lesions in mice transplanted with ABCA1 overexpressing bone marrow were still 1.6-fold smaller (393+/-27x10(3) microm2 compared with 640+/-59x10(3) microm2 in control transplanted mice; P=0.0015).


CONCLUSIONS
ABCA1 upregulation in macrophages inhibits the progression of atherosclerotic lesions.
Van Eck
Miranda
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. M.Eck@LACDR.LeidenUniv.nl
Singaraja
Roshni R
RR
Ye
Dan
D
Hildebrand
Reeni B
RB
James
Erick R
ER
Hayden
Michael R
MR
Van Berkel
Theo J C
TJ
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D011973:Receptors, LDL