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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.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

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