Inhibition of protein kinase Cβ prevents foam cell formation by reducing scavenger receptor A expression in human macrophages

Elena Osto, Alexei Kouroedov, Pavani Mocharla, Alexander Akhmedov, Christian Besler, Lucia Rohrer, Arnold Von Eckardstein, Sabino Iliceto, Massimo Volpe, Thomas F. Lüscher, Francesco Cosentino

Research output: Contribution to journalArticle

Abstract

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 Cβ (PKCβ) is involved in many mechanisms promoting atherosclerosis. Thus, we investigated whether inhibition of PKCβ 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 Dil-modified LDL (acetylated LDL and oxidized LDL, 10 μg/mL) led to lipoprotein uptake. Interestingly enough, the nonselective inhibitor of PKCβ 1 and PKCβ 2, LY379196 (5 × 10 -7 to 10 -5 mol/L), blunted LDL uptake in monocyte-derived macrophages as shown by flow cytometry. Specific siRNA-mediated knockdown of PKCβ 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 PKCβ 2, did not affect LDL uptake, nor did it prevent scavenger receptor A upregulation. Incubation of monocyte-derived macrophages with PMA/LDL increased PKCβ 1 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-α release, or superoxide anion production, ruling out any effect of PKCβ inhibition on innate immunity. Conclusions - Nonspecific inhibition of PKCβ prevents LDL uptake in macrophages. These findings suggest that PKCβ inhibitors may represent a novel class of antiatherosclerotic drugs.

Original languageEnglish
Pages (from-to)2174-2182
Number of pages9
JournalCirculation
Volume118
Issue number21
DOIs
Publication statusPublished - Nov 18 2008

Keywords

  • Atherosclerosis
  • Foam cells
  • Lipoproteins, LDL
  • Macrophages
  • Protein kinase C
  • Receptors, scavenger

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Osto, E., Kouroedov, A., Mocharla, P., Akhmedov, A., Besler, C., Rohrer, L., Von Eckardstein, A., Iliceto, S., Volpe, M., Lüscher, T. F., & Cosentino, F. (2008). Inhibition of protein kinase Cβ prevents foam cell formation by reducing scavenger receptor A expression in human macrophages. Circulation, 118(21), 2174-2182. https://doi.org/10.1161/CIRCULATIONAHA.108.789537