TY - JOUR
T1 - Inhibition of protein kinase Cβ prevents foam cell formation by reducing scavenger receptor A expression in human macrophages
AU - Osto, Elena
AU - Kouroedov, Alexei
AU - Mocharla, Pavani
AU - Akhmedov, Alexander
AU - Besler, Christian
AU - Rohrer, Lucia
AU - Von Eckardstein, Arnold
AU - Iliceto, Sabino
AU - Volpe, Massimo
AU - Lüscher, Thomas F.
AU - Cosentino, Francesco
PY - 2008/11/18
Y1 - 2008/11/18
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Foam cells
KW - Lipoproteins, LDL
KW - Macrophages
KW - Protein kinase C
KW - Receptors, scavenger
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UR - http://www.scopus.com/inward/citedby.url?scp=57449106477&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.108.789537
DO - 10.1161/CIRCULATIONAHA.108.789537
M3 - Article
C2 - 18981301
AN - SCOPUS:57449106477
VL - 118
SP - 2174
EP - 2182
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 21
ER -