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Journal of Lipid Research, Vol. 45, 1768-1776, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Effect of macrophage differentiation and exposure to mildly oxidized LDL on the proteolytic repertoire of THP-1 monocytes

Carl Whatling^*, Hanna Björk^*, Sara Gredmark, Anders Hamsten^* and Per Eriksson^1,*

^* Atherosclerosis Research Unit, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden
Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden

¹ To whom correspondence should be addressed. e-mail: per.eriksson{at}medks.ki.se

Lipid-laden monocyte/macrophages in atherosclerotic plaques can produce a range of proteinases capable of degrading components of the plaque extracellular matrix, an event that may weaken plaques, rendering them vulnerable to rupture. The effects of differentiation from monocytes to macrophages and exposure to mildly oxidized LDL (Ox-LDL) on the expression of a range of proteinases and their inhibitors were assessed in the human THP-1 cell line. Of 56 proteinases/inhibitors investigated, 17 were upregulated during macrophage differentiation, including several matrix metalloproteinases (MMPs) and cathepsins along with their native inhibitors. Similarly, expression of matrix-degrading proteinases was also increased during differentiation of human primary macrophages. In conjunction, the proteolytic capacity of the cells increased, as assessed by substrate zymography. Subsequent exposure of differentiated THP-1 cells to mildly Ox-LDL increased the expression of a control gene (adipocyte lipid binding protein) and increased the activity of nuclear factor-B and activator protein-1 in serum-free conditions but did not significantly affect the expression of any of the proteinases or inhibitors investigated.

These results indicate that in this model macrophage differentiation, rather than exposure to Ox-LDL, has a more important effect on the expression of genes involved in extracellular matrix remodeling.

Abbreviations: ALBP, adipocyte lipid binding protein; AP-1, activator protein-1; ECM, extracellular matrix; EMSA, electrophoretic mobility shift assay; MDA, malondialdehyde; MMP, matrix metalloproteinase; NFB, nuclear factor-B; Ox-LDL, oxidized low density lipoprotein; PBMC, peripheral blood mononuclear cell; TBARS, thiobarbituric acid-reactive species; TIMP, tissue inhibitor of matrix metalloproteinases

Supplementary key words atherosclerosis • proteinases • matrix metalloproteinase • cathepsin • microarray • low density lipoprotein

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