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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-6875

Osto, E; Kuroedov, 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 Cbeta prevents foam cell formation by reducing scavenger receptor A expression in human macrophages. Circulation, 118(21):2174-2182.

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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 Cbeta (PKCbeta) is involved in many mechanisms promoting atherosclerosis. Thus, we investigated whether inhibition of PKCbeta 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 mug/mL) led to lipoprotein uptake. Interestingly enough, the nonselective inhibitor of PKCbeta(1) and PKCbeta(2), 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 PKCbeta 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 PKCbeta(2), did not affect LDL uptake, nor did it prevent scavenger receptor A upregulation. Incubation of monocyte-derived macrophages with PMA/LDL increased PKCbeta(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 PKCbeta inhibition on innate immunity. CONCLUSIONS: Nonspecific inhibition of PKCbeta prevents LDL uptake in macrophages. These findings suggest that PKCbeta inhibitors may represent a novel class of antiatherosclerotic drugs.

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26 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Integrative Human Physiology
04 Faculty of Medicine > University Hospital Zurich > Institute of Clinical Chemistry
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
DDC:570 Life sciences; biology
610 Medicine & health
540 Chemistry
Language:English
Date:18 November 2008
Deposited On:05 Dec 2008 12:31
Last Modified:27 Nov 2013 23:49
Publisher:American Heart Association
ISSN:0009-7322
Funders:Swiss National Research Foundation, Swiss Heart Foundation
Additional Information:This is an un-copyedited author manuscript that was accepted for publication in Circulation, copyright The American Heart Association. This may not be duplicated or reproduced, other than for personal use or within the “Fair Use of Copyrighted Materials” (section 107, title 17, U.S. Code) without prior permission of the copyright owner, The American Heart Association. The final copyedited article, which is the version of record, can be found at http://circ.ahajournals.org/cgi/content/abstract/118/21/2174. The American Heart Association disclaims any responsibility or liability for errors or omissions in this version of the manuscript or in any version derived from it by the National Institutes of Health or other parties.
Publisher DOI:10.1161/CIRCULATIONAHA.108.789537
PubMed ID:18981301

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