Inhibition of Protein Kinase C beta Prevents Foam Cell Formation by Reducing Scavenger Receptor A Expression in Human Macrophages

Article

关键词: ENDOTHELIUM-DEPENDENT VASODILATION;    ISOZYME-SELECTIVE INHIBITORS;    LOW-DENSITY-LIPOPROTEIN;    PKC-BETA;    HIGH GLUCOSE;    DIABETIC COMPLICATIONS;    NAD(P)H OXIDASE;    RUBOXISTAURIN;    ACTIVATION;    PATHOPHYSIOLOGY;   

DOI  :  10.1161/CIRCULATIONAHA.108.789537

来源: SCIE

【 摘 要 】

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 beta (PKC beta) is involved in many mechanisms promoting atherosclerosis. Thus, we investigated whether inhibition of PKC beta 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 mu g/mL) led to lipoprotein uptake. Interestingly enough, the nonselective inhibitor of PKC beta(1) and PKC beta(2), LY379196 (5 x 10(-7) to 10(-5) mol/L), blunted LDL uptake in monocyte-derived macrophages as shown by flow cytometry. Specific siRNA-mediated knockdown of PKC beta 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 PKC beta(2), did not affect LDL uptake, nor did it prevent scavenger receptor A upregulation. Incubation of monocyte-derived macrophages with PMA/LDL increased PKC beta(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-alpha release, or superoxide anion production, ruling out any effect of PKC beta inhibition on innate immunity. Conclusions-Nonspecific inhibition of PKC beta prevents LDL uptake in macrophages. These findings suggest that PKC beta inhibitors may represent a novel class of antiatherosclerotic drugs. (Circulation. 2008; 118: 2174-2182.)

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