2-Aminopurine Inhibits Lipid Accumulation Induced By Apolipoprotein E-Deficient Lipoprotein In Macrophages: Potential Role Of Eukaryotic Initiation Factor-2 Alpha 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)-2 alpha 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-2 alpha 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-2 alpha 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-2 alpha phosphorylation.