%0 Journal Article %A DongFang Wu %A Hong Yang %A YanFeng Zhao %A Chakradhari Sharan %A J. Shawn Goodwin %A Lichun Zhou %A Yang Guo %A ZhongMao Guo %T 2-Aminopurine Inhibits Lipid Accumulation Induced by Apolipoprotein E-Deficient Lipoprotein in Macrophages: Potential Role of Eukaryotic Initiation Factor-2α Phosphorylation in Foam Cell Formation %D 2008 %R 10.1124/jpet.107.134833 %J Journal of Pharmacology and Experimental Therapeutics %P 395-405 %V 326 %N 2 %X 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)-2α 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-2α 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-2α 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-2α phosphorylation. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/326/2/395.full.pdf