© 1995 American Heart Association, Inc.
Articles |
Human Vascular Smooth Muscle Cell–Monocyte Interactions and Metalloproteinase Secretion in Culture
From the Harvard-MIT Division of Health Sciences and Technology, Cambridge, Mass (E.L., A.J.G., R.T.L.); the Department of Mechanical Engineering, MIT, Cambridge, Mass (A.J.G., R.T.L.); the Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (P.L., R.T.L.); the Dana-Farber Cancer Institute, Boston, Mass (S.K.C.); and Merck Research Laboratories, Rahway, NJ (M.W.L.).
Correspondence to Richard T. Lee, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail rtlee@bics.bwh.harvard.edu.
Abstract Degradation of the atherosclerotic plaque
extracellular matrix could destabilize the lesion, rendering it more
prone to rupture. Both macrophages and vascular smooth muscle
cells (SMCs) are potential sources of matrix metalloproteinases (MMPs),
secreted enzymes that can digest vascular matrix. We explored
interactions between human vascular SMCs and human monocytes that
result in the secretion of interstitial
collagenase (MMP-1) and stromelysin (MMP-3). Monocytes
alone or those treated with SMC-conditioned media did not secrete these
metalloproteinases as detectable by Western blot analysis. SMCs
increased secretion of both MMP-1 and MMP-3 greater than 20-fold when
cocultured with monocytes or when treated with monocyte-conditioned
media. Addition of macrophage colony stimulating factor (
1000
U/mL) to cocultures of monocytes and SMCs did not affect
metalloproteinase secretion. Recombinant interleukin (IL)-1 receptor
antagonist inhibited MMP-1 and MMP-3 induction in SMC
cultures treated with monocyte-conditioned media (94% and 96%
reduction, respectively), while a neutralizing antibody to tumor
necrosis factor-
had no significant effect on metalloproteinase
secretion. In contrast to the induction by monocyte-conditioned
media of MMP-1 and MMP-3 secretion by SMCs, monocyte-conditioned
media did not increase secretion of 72-kD gelatinase (MMP-2). Thus,
monocytes induce MMP-1 and MMP-3 secretion by vascular SMCs through an
IL-1–dependent mechanism. This response of SMCs to a defined
macrophage product may contribute to plaque destabilization
by mononuclear phagocytes in the lesion.
Key Words: monocytes • vascular smooth muscle cells • metalloproteinases • plaque rupture
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