© 1997 American Heart Association, Inc.
Articles |
Regulation of Matrix Metalloproteinase Expression in Human Vascular Smooth Muscle Cells by T Lymphocytes
A Role for CD40 Signaling in Plaque Rupture?
From the Vascular Medicine and Atherosclerosis Unit (U.S., F.M., G.K.S., C.M., R.P.F., P.L.), Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass, and the Geneva (Switzerland) Biomedical Research Institute (J.-Y.B.).
Correspondence to Peter Libby, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}bustoff.bwh.harvard.edu
Abstract Physical disruption of an
atheromatous lesion often underlies acute
coronary syndromes. Matrix-degrading enzymes, eg, matrix
metalloproteinases (MMPs), may cause loss in mechanical integrity of
plaque tissue that favors rupture. T lymphocytes accumulate at sites
where atheromata rupture, but the mechanisms by which these
immune cells may contribute to plaque destabilization are unknown. This
study tested the hypothesis that the T-lymphocyte surface molecule CD40
ligand (CD40L), recently localized in atherosclerotic plaques,
regulates the expression of MMPs in human vascular smooth muscle cells
(SMCs), the most numerous cell type in arteries. We report here that
stimulated human T lymphocytes induced the expression of the
matrix-degrading enzymes, ie, interstitial
collagenase (MMP-1), stromelysin (MMP-3), gelatinase B
(MMP-9), and activated gelatinase A (MMP-2), in human vascular
SMCs by cell contact via CD40 ligation, as demonstrated by Western blot
analysis, zymography, and antibody neutralization. Recombinant
human CD40L (rCD40L) induced de novo synthesis of MMP-1, MMP-3, and
MMP-9 on vascular SMCs and stimulated the expression of these enzymes
to a greater extent than did maximally effective concentrations of
tumor necrosis factor-
or interleukin-1ß, established agonists of
MMP expression. Interferon gamma, another T-lymphocyte–derived
cytokine, inhibited the induction of MMPs by rCD40L.
Immunohistochemical analysis of human coronary
atheromata colocalized MMP-1 and MMP-3 with CD40-positive
SMCs. These results demonstrated that CD40 ligand, expressed on T
lymphocytes, promoted the expression of matrix-degrading enzymes in
vascular SMCs and thus established a new pathway of immune-modulated
destabilization in human atheromata.
Key Words: matrix metalloproteinase • smooth muscle cell • CD40 ligand • atherosclerosis
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