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(Circulation. 2008;118:2174-2182.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

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

Elena Osto, MD^*; Alexei Kouroedov, MD, PhD^*; Pavani Mocharla, MS; Alexander Akhmedov, PhD; Christian Besler, MD; Lucia Rohrer, PhD; Arnold von Eckardstein, MD; Sabino Iliceto, MD; Massimo Volpe, MD; Thomas F. Lüscher, MD; Francesco Cosentino, MD, PhD

From the Department of Cardiology, University Hospital and Cardiovascular Research, Institute of Physiology, and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland (E.O., A.K., P.M., A.A., C.B., T.F.L., F.C.); Institute of Clinical Chemistry, University Hospital, Zürich, Switzerland (L.R., A.v.E.); Department of Cardiology, University of Padova (S.I.); Department of Cardiology, Second Faculty of Medicine, University "Sapienza," Rome, Italy (M.V., F.C.); and IRCCS Neuromed, Pozzilli, Italy (M.V.).

Correspondence to Francesco Cosentino, MD, PhD, Cardiovascular Research, Institute of Physiology, University of Zürich-Irchel, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail f_cosentino{at}hotmail.com

Received June 20, 2007; accepted September 2, 2008.

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 DiI-modified LDL (acetylated LDL and oxidized LDL, 10 µg/mL) led to lipoprotein uptake. Interestingly enough, the nonselective inhibitor of PKCβ₁ and PKCβ₂, 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 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 PKCβ₂, did not affect LDL uptake, nor did it prevent scavenger receptor A upregulation. Incubation of monocyte-derived macrophages with PMA/LDL increased PKCβ₁ 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 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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
Circulation 2008 118: 2115-2116. [Extract] [Full Text]