Published online before print October 30, 2003, doi: 10.1161/01.ATV.0000104014.24367.16
© 2004 American Heart Association, Inc.
Vascular Biology |
C-Reactive Protein Stimulates MMP-1 Expression in U937 Histiocytes Through Fc
RII and Extracellular Signal-Regulated Kinase Pathway:
An Implication of CRP Involvement in Plaque Destabilization
From the Ralph H. Johnson Veterans Affairs Medical Center and Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine Medical University of South Carolina, Charleston, SC.
Correspondence to Yan Huang, MD, PhD, Ralph H. Johnson Veterans Affairs Medical Center and Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29403. E-mail huangyan{at}musc.edu
Objective— It has been shown that plasma level of C-reactive protein (CRP) is an independent predictor for acute coronary syndromes and is associated with plaque weakening. However, the underlying mechanisms are not well understood. In this study, we investigated the effect of CRP on the expression of matrix metalloproteinase-1 (MMP-1) that has been implicated in plaque vulnerability by human U937 histiocytes and monocyte-derived macrophages.
Methods and Results— Enzyme-linked immunosorbent assay of MMP-1 in conditioned medium showed that treatment of U937 cells with 100 µg/mL of CRP for 24 hour led to a 3- to 5-fold increase in MMP-1 secretion. CRP also markedly stimulated MMP-1 release from human monocyte-derived macrophages. In contrast, CRP had no effect on tissue inhibitor of metalloproteinase-1 (TIMP-1) secretion. Northern blot showed that CRP upregulated MMP-1 mRNA expression. Collagenase activity assay showed that CRP increased collagen-degrading activity in cell-conditioned medium. Furthermore, results showed that the stimulation of MMP-1 secretion by CRP was inhibited by anti-CD32, but not by anti-CD64 antibody, and by mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor PD98059. Finally, Western blot showed that CRP stimulated phosphorylation of extracellular signal-regulated kinase.
Conclusions— This study demonstrates that CRP stimulates MMP-1 expression by U937 cells through Fc
RII and extracellular signal-regulated kinase pathway. These findings suggest that CRP may promote matrix degradation and thus contribute to plaque vulnerability.
Key Words: C-reactive protein • matrix metalloproteinase • arteriosclerosis • gene expression
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