Erythropoietin suppresses the formation of macrophage foam cells: role of liver X receptor alpha.
BACKGROUND
In addition to the hematopoietic effect of erythropoietin, increasing evidence suggests that erythropoietin also exerts protective effects for cardiovascular diseases. However, the role of erythropoietin and its underlying mechanism in macrophage foam cell formation are poorly understood.


RESULTS
Compared with wild-type specimens, erythropoietin was increased in atherosclerotic aortas of apolipoprotein E-deficient (apoE(-/-)) mice, mainly in the macrophage foam cells of the lesions. Erythropoietin levels in culture medium and macrophages were significantly elevated in response to oxidized low-density lipoprotein in a dose-dependent manner. Furthermore, erythropoietin markedly attenuated lipid accumulation in oxidized low-density lipoprotein-treated macrophages, a result that was due to an increase in cholesterol efflux. Erythropoietin treatment significantly increased ATP-binding cassette transporters (ABC) A1 and ABCG1 mRNA and protein levels without affecting protein expression of scavenger receptors, including scavenger receptor-A, CD36, and scavenger receptor-BI. The upregulation of ABCA1 and ABCG1 by erythropoietin resulted from liver X receptor alpha activation, which was confirmed by its prevention on expression of ABCA1 and ABCG1 after pharmacological or small interfering RNA inhibition of liver X receptor alpha. Moreover, the erythropoietin-mediated attenuation on lipid accumulation was abolished by such inhibition. Finally, reduced lipid accumulation and marked increase in ABCA1 and ABCG1 were demonstrated in erythropoietin-overexpressed macrophages.


CONCLUSIONS
Our data suggest that erythropoietin suppresses foam cell formation via the liver X receptor alpha-dependent upregulation of ABCA1 and ABCG1.
Lu
Kuo-Yun
KY
Department of Physiology, National Yang-Ming University, Taipei 112, Taiwan. tslee@ym.edu.tw
Ching
Li-Chieh
LC
Su
Kuo-Hui
KH
Yu
Yuan-Bin
YB
Kou
Yu Ru
YR
Hsiao
Sheng-Huang
SH
Huang
Yu-Chu
YC
Chen
Chien-Yu
CY
Cheng
Li-Ching
LC
Pan
Ching-Chian
CC
Lee
Tzong-Shyuan
TS
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001018:Aortic Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018955:CD36 Antigens / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004921:Erythropoietin / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008055:Lipids / Q000096:biosynthesis; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000235:genetics
C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018955:CD36 Antigens; D002316:Cardiotonic Agents; D008055:Lipids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; C099252:oxidized low density lipoprotein; D004921:Erythropoietin