2-Aminopurine inhibits lipid accumulation induced by apolipoprotein E-deficient lipoprotein in macrophages: potential role of eukaryotic initiation factor-2alpha phosphorylation in foam cell formation.
We previously reported that apolipoprotein (Apo) E-deficient, ApoB48-containing (E(-)/B48) lipoproteins inhibited expression of lysosomal hydrolase and transformed mouse peritoneal macrophages (MPMs) into foam cells. The present study examined the effect of 2-aminopurine (2-AP), an inhibitor of eukaryotic initiation factor (eIF)-2alpha phosphorylation, on E(-)/B48 lipoprotein-induced changes in gene expression and foam cell formation. Our data demonstrated that E(-)/B48 lipoproteins enhanced phosphorylation of eIF-2alpha in macrophages. Incubation of MPMs with E(-)/B48 lipoproteins inhibited the translation efficiency of mRNAs encoding lysosomal acid lipase, cathepsin B, and cation-dependent mannose 6 phosphate receptor, with a parallel reduction in the level of these proteins. Addition of 2-AP to the culture media alleviated the suppressive effect of E(-)/B48 lipoproteins on lysosomal hydrolase mRNA translation, increased macrophage degradation of E(-)/B48 lipoproteins, and inhibited foam cell formation. Transfection of MPMs with a nonphosphorylatable eIF-2alpha mutant also attenuated the suppressive effect of E(-)/B48 lipoproteins on expression of lysosomal acid lipase, associated with a reduced accumulation of cellular cholesterol esters. This is the first demonstration that ApoE-deficient lipoproteins inhibit lysosomal hydrolase synthesis and transform macrophages into foam cells through induction of eIF-2alpha phosphorylation.
Wu
Dongfang
D
Department of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208, USA.
Yang
Hong
H
Zhao
Yanfeng
Y
Sharan
Chakradhari
C
Goodwin
J Shawn
JS
Zhou
Lichun
L
Guo
Yang
Y
Guo
Zhongmao
Z
D015075:2-Aminopurine / Q000494:pharmacology*; D000818:Animals; D053283:Apolipoprotein B-48 / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D014162:Transfection
D053283:Apolipoprotein B-48; D001057:Apolipoproteins E; D015852:Eukaryotic Initiation Factor-2; D015075:2-Aminopurine