Background—Low-density lipoprotein (LDL) uptake by monocyte-derived macrophages is a crucial step in foam cell formation and early atherosclerotic lesion. Increasing evidence supports the theory that activation of protein kinase C (PKC) is involved in many mechanisms promoting atherosclerosis. Thus, we investigated whether inhibition of PKC prevents foam cell formation.

Methods and Results—The differentiation of human primary monocytes or the monocytic THP-1 cell line into monocyte-derived macrophages was induced by phorbol 12-myristate 13-acetate (PMA; 0.1 mmol/L), a potent activator of PKC. Incubation of monocyte-derived macrophages with DiI-modified LDL (acetylated LDL and oxidized LDL, 10 µg/mL) led to lipoprotein uptake. Interestingly enough, the nonselective inhibitor of PKC₁ and PKC₂, LY379196 (5x10^-7 to 10^-5 mol/L), blunted LDL uptake in monocyte-derived macrophages as shown by flow cytometry. Specific siRNA-mediated knockdown of PKC exerted a similar effect. Furthermore, PMA alone and in the presence of modified LDL induced scavenger receptor A mRNA and protein expression, which was abolished by LY379196. CGP53353, a selective inhibitor of PKC₂, did not affect LDL uptake, nor did it prevent scavenger receptor A upregulation. Incubation of monocyte-derived macrophages with PMA/LDL increased PKC₁ phosphorylation at the Thr-642 residue, which was blunted by LY379196. However, the expression of CD68, a marker of activated macrophages, was not affected by LY379196. Moreover, LY379196 did not affect lipopolysaccharide-induced CD14 degradation, tumor necrosis factor- release, or superoxide anion production, ruling out any effect of PKC inhibition on innate immunity.

Conclusions—Nonspecific inhibition of PKC prevents LDL uptake in macrophages. These findings suggest that PKC inhibitors may represent a novel class of antiatherosclerotic drugs.