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CARDIOVASCULAR

2-Aminopurine Inhibits Lipid Accumulation Induced by Apolipoprotein E-Deficient Lipoprotein in Macrophages: Potential Role of Eukaryotic Initiation Factor-2 Phosphorylation in Foam Cell Formation

Department of Cardiovascular Biology (D.W., H.Y., Y.Z., C.S., L.Z., Y.G., Z.G.), Morphology Core Facility and Department of Cancer Biology (J.S.G.), Meharry Medical College, Nashville, Tennessee

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 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, 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 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.

Address correspondence to: Dr. ZhongMao Guo, Department of Cardiovascular Biology, Meharry Medical College, Nashville, TN 37208. E-mail: ZGUO{at}mmc.edu