Received for publication November 30, 2007.
Revised May 6, 2008.
Accepted for publication May 6, 2008.

2-Aminopurine inhibits lipid accumulation induced by apolipoprotein E-deficient lipoprotein in macrophages: potential role of eIF-2 phosphorylation in foam cell formation

Abstract

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-2(eIF-2) 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 in macrophages. Incubation of MPMs with E/B48 lipoproteins inhibited the translation efficiency of mRNAs encoding lysosomal acid lipase, capthesin B and cation-dependent mannose 6 phosphate receptor (MPR46), 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 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 phosphorylation.

Key words: 2-aminopurine, apolipoprotein E-deficient lipoproteins, eukaryotic initiation factor-2alpha, foam cells, lysosomal hydrolase, macrophages