© 1996 American Heart Association, Inc.
Articles |
Regulation of Matrix Metalloproteinases and Plasminogen Activator Inhibitor-1 Synthesis by Plasminogen in Cultured Human Vascular Smooth Muscle Cells
From the Harvard-MIT Division of Health Sciences and Technology (E.L., A.J.G., R.T.L.), Cambridge, Mass; the Cardiology Division (D.E.V.), Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tenn; the Cardiovascular Division (S.H.P., P.L., R.T.L.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; and Merck Research Laboratories (M.W.L.), Rahway, NJ.
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.
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Abstract |
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 Top Abstract IntroductionMaterials and Methods Results Discussion References |
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Abstract Plasmin and matrix metalloproteinases (MMPs) both participate in extracellular matrix remodeling. This study examined the effects of tumor necrosis factor-
(TNF-) and
plasminogen on collagenase, stromelysin, and
plasminogen activator inhibitor-1
(PAI-1) synthesis by cultured human vascular smooth muscle cells
(SMCs). TNF- induced the concentration-dependent synthesis of
collagenase and stromelysin, which remained predominantly
in proenzyme forms, as determined by Western analysis of
culture media. In contrast, plasminogen and plasmin not
only increased secretion of MMPs but also induced cleavage to their
active forms. The serine protease inhibitor aprotinin
inhibited this activation of MMPs by plasminogen and
plasmin. TNF- reduced plasminogen-induced activation
of MMPs, suggesting induction of an inhibitor of plasmin
generation, such as PAI-1. Enzyme-linked immunosorbent assay of
culture media showed that TNF- (10 ng/mL) increased PAI-1 secretion
by 4.2-fold compared with control (105.5±9.6 versus 24.9±1.7
ng/mL,
n=3). Surprisingly, plasminogen also increased PAI-1
secretion by vascular SMCs (3.6-fold over control). These results
demonstrate coordination of cytokines and serine proteases in
regulating MMP secretion and activation. In addition, the induction of
PAI-1 by TNF- and plasminogen suggests a
negative-feedback mechanism to limit both plasmin-mediated and
MMP-mediated matrix degradation.
Key Words: collagenase • stromelysin • vascular smooth muscle • plasmin • plasminogen
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Introduction |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Vascular remodeling occurs in response to hemodynamic stimuli, biochemical mediators, or injury.1 Remodeling may involve changes in the number and distribution of cells as well as changes in the quantity and composition of extracellular matrix. The modification of extracellular matrix depends on both synthesis and degradation of matrix molecules. In vascular tissue, SMCs synthesize collagen and proteoglycans, the principal components of vascular matrix.2 3 Interstitial collagenase and stromelysin are MMPs, which degrade matrix components, and SMCs can produce these proteases.4 5 Macrophages, which can accumulate in diseased vascular tissue, may also be an important source of MMPs.6
The MMPs are secreted in zymogen form and require extracellular activation. The serine protease plasmin can activate latent collagenase and stromelysin in vitro and may perform this role in vivo in some tissues.7 8 Plasmin, in turn, must be generated from plasminogen by plasminogen activators, and plasmin may directly degrade several components of extracellular matrix. Vascular SMCs can synthesize plasminogen activators as well as plasminogen activator inhibitors.9 10 Plasmin may also regulate remodeling beyond its role in activating latent MMPs; Werb and Aggeler11 reported that cultured fibroblasts treated with plasmin increase collagenase secretion. Therefore, regulation of vascular extracellular matrix degradation can occur at multiple levels involving the secretion and activation of MMPs. Furthermore, TIMPs may inhibit the activity of the activated enzymes.
Several cytokines potently modulate extracellular matrix
synthesis and degradation. For example, interleukin-1,
platelet-derived growth factor, and transforming growth
factor-ß increase the synthesis of collagen and proteoglycans by
cultured vascular
SMCs.12 13 14 15 16
Interleukin-1 and TNF-
also induce interstitial collagenase and
stromelysin synthesis by vascular SMCs.17 Since these
cytokines are present in the blood vessel wall in certain
pathological conditions, these observations may have in vivo
relevance.
The present study investigated the role of plasminogen,
with and without TNF-, on the synthesis and activation of MMPs by
cultured human vascular SMCs. We report that both
plasminogen and TNF- induce the synthesis of
collagenase and stromelysin and that
plasminogen also induces cleavage of the latent MMPs to the
active forms. In addition, both plasminogen and TNF-
induce PAI-1, providing a negative-feedback mechanism for the
matrix degradation response. These results demonstrate coordination of
cytokines and serine proteases in regulating matrix remodeling
by MMPs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Materials
DMEM, Ham's F-12 medium, and Limulus amebocyte lysate test kit were obtained from BioWhittaker; fetal calf serum, from Hyclone Laboratories; tissue culture dishes, from Costar; ascorbate-2-phosphate, from Wako Pure Chemical Industries; nonessential amino acids, human Lys-plasminogen, kringle 1-3 and kringle 4 from human plasminogen, aprotinin, and endotoxin from Escherichia coli 0111:B4, from Sigma Chemical Co; insulin and transferrin, from Collaborative Research; TNF-
, from
Genzyme; plasmin and goat anti-human plasminogen IgG,
from Enzyme Research Laboratories; Centricon-10 microconcentrators,
from Amicon; enhanced chemiluminescence detection system, from
Amersham; goat anti-rabbit IgG antibody with horseradish
peroxidase, from Bio-Rad Laboratories; and ELISA kits, from Biopool AB.
Rabbit anti-human antibodies to human collagenase and
stromelysin were prepared as previously described.18
Cell Culture
Medial-layer explants were cultured from unused
portions of
human saphenous veins from coronary bypass surgery. The culture
medium was DMEM with 10% fetal calf serum, 25 mmol/L HEPES, 100 U/mL
penicillin, 100 µg/mL streptomycin, 1.25 µg/mL amphotericin B, and
2 mmol/L L-glutamine. This medium is selective for SMCs
over endothelial cells.19 Cells in some
experiments were stained for -actin. Unlike cultured rat
vascular SMCs, cultured human vascular SMCs do not uniformly stain for
-actin. Approximately 50% of cells in the present study
stained positively; this level is similar to other human vascular SMC
preparations in our laboratories. Human dermal fibroblasts used as a
control did not stain for -actin (<5%).
SMCs from the explants were grown in tissue culture flasks. At confluence, the cells were split 1:3 by using 0.25% trypsin and EDTA. The cells were cultured in monolayers for two to six passages before use in experiments.
Treatment With Plasminogen and TNF-
Cells were plated in
22- or 35-mm culture wells at 1 to
2.5x104 cells per square centimeter and 0.26
mL/cm2 of medium. The medium was the same as that described
above and was further supplemented with 0.07 mmol/L
ascorbate-2-phosphate, 0.1 mmol/L nonessential amino acids, and 0.75
mmol/L sodium sulfate. After 2 days, the medium was removed and
replaced with 0.13 mL/cm2 of fresh medium. After 2 more
days, serum was removed from the wells by washing four times with 0.26
mL/cm2 of IT medium (equal volumes of DMEM and Ham's F-12,
with 12.5 mmol/L HEPES, 100 U/mL penicillin, 100 µg/mL streptomycin,
1.25 µg/mL amphotericin B, 1.5 mmol/L L-glutamine, 0.07
mmol/L ascorbate-2-phosphate, 0.1 mmol/L nonessential amino acids, 0.75
mmol/L sodium sulfate, 1 µmol/L insulin, and 5 µg/mL transferrin).
After the last wash, 0.13 mL/cm2 of IT medium was added to
each well. The IT medium was changed at 24 hours. At 48 hours, the IT
medium was changed again, and human plasminogen and/or
recombinant human TNF- was added to the wells. Cells were also
treated with human plasminogen kringles, human plasmin, or
aprotinin in some experiments. The media were collected after 24 hours
of treatment. Some wells were counted for total and viable cells by
using trypan blue exclusion after collagenase and trypsin
digestion of the cell layer; none of the treatments significantly
changed cell numbers or cell viability. Each treatment was performed at
least twice in independent experiments.
Because bacterial endotoxin can
induce a variety of products,
including MMPs and PAI-1,20 21 22 unused
media containing 100
µg/mL of plasminogen or plasmin were assayed for
endotoxin by using the chromogenic Limulus
amebocyte lysate test.23 The plasminogen
sample contained 8 pg/mL, and the plasmin sample contained 56 pg/mL
endotoxin. Unused medium containing 2 trypsin inhibitor
units per milliliter of aprotinin was similarly assayed and contained
150 pg/mL endotoxin. TNF- is tested by the manufacturer for
endotoxin level by gel clot test, and a concentration of 10 ng/mL
TNF- contains 0.02 pg/mL endotoxin. To test for possible effects due
to the contaminating endotoxin, some cells were treated for 24 hours
with up to 10 ng/mL of endotoxin from E coli; no significant
effect on PAI-1 or MMP synthesis was seen at the concentrations of
endotoxin in these studies.
Electrophoresis and Immunoblotting (Western
Analysis)
Because the levels of response varied with the cell source
in
these primary cultures of SMCs, media samples from a TNF-
concentration-response experiment were concentrated up to 20-fold
in Centricon-10 centrifugal microconcentrators. All other samples were
analyzed without concentration. Samples underwent
electrophoresis on SDS–10% polyacrylamide gels under reducing
conditions (SDS-PAGE). The proteins were transferred to nitrocellulose
membranes, and an enhanced chemiluminescence detection system
was used to detect collagenase or stromelysin. A 5%
solution of nonfat dried milk in PBS containing 0.1% Tween 20 was used
to block nonspecific binding and to dilute the primary and secondary
antibodies. The primary antibodies were rabbit anti-human
collagenase IgG (0.97 µg/µL, diluted 1:800 or 1:600)
and rabbit anti-human stromelysin antiserum (diluted 1:400). The
secondary antibody was goat anti-rabbit IgG conjugated with
horseradish peroxidase.
ELISA for PAI-1
Media samples were assayed for PAI-1 as
previously
described.24 In brief, samples were incubated in
microtiter plates coated with monoclonal antibodies against PAI-1,
unbound antigen was washed off, and bound antigen was detected by
addition of a second specific antibody conjugated to horseradish
peroxidase. Standard curves were constructed from dilutions of purified
PAI-1.
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Results |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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Effect of Plasminogen and Plasmin on MMP Secretion and Activation
Western blot analysis demonstrated that plasminogen induced secretion of both collagenase and stromelysin in a concentration-dependent manner in vascular SMCs (Fig 1
). In the
absence of plasminogen, SMCs
secreted little collagenase in its latent glycosylated and
unglycosylated forms, although the lower molecular weight
activated forms of the enzymes were not detectable (Fig 1A).
Total collagenase secretion increased with
plasminogen concentration, although the absolute amounts
varied among experiments using SMCs from different sources. These
differences are explained by the variability in the magnitude of
response to stimuli in primary cultures of SMCs.
Plasminogen levels of 50 or 100 µg/mL, depending on the
particular experiment, were sufficient to cause activation of the
collagenase to the smaller forms. The response of
stromelysin secretion to plasminogen was similar (Fig 1B).
Total stromelysin levels increased with plasminogen
concentration. The unglycosylated and glycosylated activated
forms appeared with 50 or 100 µg/mL plasminogen, but only
the latent forms appeared at lower concentrations. Some
cross-reactivity of the stromelysin antiserum with plasmin is
evident near 60 kD.
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To explore further the induction of MMPs, vascular
SMCs were cultured
with plasmin (Fig 2). As in the experiments with
plasminogen, Western blot analysis of the culture
media showed that both collagenase and stromelysin were
induced in a concentration-dependent manner by plasmin;
furthermore, activation of the proenzymes to the active forms was also
concentration dependent. Some cross-reactivity of the
collagenase antiserum with plasmin is evident near 60
kD.
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Treatment of the SMCs with plasminogen lysine-binding-site fragments was performed to examine the possibility of a direct effect of plasminogen on MMP secretion. Kringle 4 did not affect MMP secretion, even at 10 times the molar concentration of plasminogen that increased MMP production (data not shown). Kringle 1-3 cross-reacted with the anti-collagenase and anti-stromelysin antisera and comigrated as a smear in the same molecular weight range as the activated MMPs.
Effect of Aprotinin on Induction of MMPs by Plasminogen
and Plasmin
The activation of collagenase and stromelysin by 100
µg/mL plasminogen or plasmin was completely blocked by
treatment with 2 trypsin inhibitor units per milliliter of
the serine protease inhibitor aprotinin (Fig 3). Unexpectedly,
aprotinin itself caused the induction
of latent MMPs in the absence of cytokines,
plasminogen, or plasmin. Plasminogen or plasmin
combined with aprotinin did not increase collagenase levels
above those induced by aprotinin alone. The results for the effects of
aprotinin on stromelysin activation were similar (data not shown).
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Effect of TNF- on MMP Secretion and Activation
Vascular
SMCs responded to 0, 0.1, 1, or 10 ng/mL TNF- with a
concentration-dependent increase of collagenase and
stromelysin (data not shown). Most of the induced MMPs were in the
latent forms, but a small amount appeared in the activated
forms. These results are consistent with those of Galis et
al,17 who reported that TNF- induced de novo synthesis
of these two enzymes by vascular SMC cultures. In the presence of 100
µg/mL plasminogen, the concentration of TNF- had
varying effects on total collagenase secretion in
experiments using SMCs from different sources. However, the trend in
activation state of collagenase was consistent
among independent experiments. Although the collagenase was
primarily in the active forms with 0, 0.1, and 1 ng/mL TNF-, most of
the collagenase appeared in the latent forms with 10 ng/mL
TNF- (Fig 4A), suggesting that TNF- induced an
inhibitor of MMP activation. The addition of TNF- to 100
µg/mL plasminogen also had varying effects on total
stromelysin secretion by SMCs in independent experiments. However, as
with collagenase, 10 ng/mL TNF- consistently
inhibited plasminogen-induced activation of
stromelysin, whereas lower concentrations of TNF- allowed most of
the stromelysin to be activated (Fig 4B).
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Effects of TNF- and Plasminogen on PAI-1
Secretion
The TNF- inhibition of MMP activation by
plasminogen suggested that TNF- increased serine
protease inhibitory activity. TNF- has been shown to
induce PAI-1 secretion in endothelial
cells.22 Therefore, measurements of PAI-1 in the culture
media were performed. As expected, TNF- induced PAI-1 in a
concentration-dependent manner; at 10 ng/mL, PAI-1 levels were
4.2-fold over control levels (Fig 5A). Surprisingly,
plasminogen (Fig 5B) also induced PAI-1 in a
concentration-dependent manner (3.6-fold over control at 100
µg/mL). The combination of TNF- and plasminogen led to
levels of PAI-1 that were significantly higher than levels reached by
either one alone (Student's t test, P<.05) but
less than would be expected if their effects were simply additive (Fig
5C). In a separate experiment, plasmin (100 µg/mL) induced
PAI-1
levels more than ninefold over control levels.
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Activity of PAI-1 Induced by TNF-
To test the activity
of the TNF-–induced PAI-1, the
conversion of plasminogen to plasmin in the absence or
presence of TNF- in SMC cultures was determined by Western blot
analysis (Fig 6). In the absence of TNF-,
plasminogen was cleaved to plasmin, although the efficiency
of the conversion varied among experiments using different sources of
SMCs. In the presence of 10 ng/mL TNF-, and therefore in the
presence of PAI-1, plasminogen activation was almost
completely blocked.
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Discussion |
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TopAbstractIntroductionMaterials and Methods Results Discussion References |
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The matrix degradation process is regulated at several levels. The MMPs are secreted in latent form and require activation, possibly by plasmin. Once the MMPs are activated, their activity may be inhibited by TIMPs. Vascular SMCs can produce not only matrix molecules and MMP zymogens but also plasminogen activators, plasminogen activator inhibitors, and TIMPs.4 Furthermore, vascular cells can vary the expression of plasminogen activator receptors to facilitate or decrease the activation of plasminogen.25 SMCs may also influence the degradation of plasminogen activators.26
In the present study, we found that plasminogen not
only increases MMP secretion and activation but also induces PAI-1
secretion in SMCs. This concentration-dependent induction of PAI-1
synthesis by plasminogen suggests a negative-feedback
mechanism for downregulating the effects of plasmin (Fig 7). If
plasmin and MMPs were not tightly regulated,
matrix degradation could proceed too rapidly for appropriate remodeling
responses by the SMCs. The secretion of PAI-1 could have the dual
negative-feedback effect of both downregulating
plasmin-mediated degradation and downregulating MMP activation.
This may provide the cell with a mechanism to control MMP activity even
after the MMPs have been synthesized and secreted into the
extracellular space. The cell specificity of this negative-feedback
mechanism warrants further study, since Etingin et al27
found no effect of plasminogen on PAI-1 secretion by
cultured vascular endothelial cells.
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Although TNF- increased MMP secretion in SMCs, the MMPs were largely
in the latent zymogen forms. We also found that TNF- at 1 ng/mL and
higher concentrations can partially inhibit the activation of MMPs,
even in the presence of plasminogen levels sufficient to
activate MMPs in the absence of TNF-. These results are
consistent with the finding that TNF- increases PAI-1,
decreasing the amount of plasmin available to activate MMPs.
Analysis by immunoblotting confirmed that PAI-1
induced by TNF- almost completely inhibited the conversion of
plasminogen to plasmin in SMC cultures. Consequently, at
higher concentrations of TNF-, there was much less plasmin available
to induce MMP secretion, such that TNF- played a greater role in
increasing MMP levels. On the other hand, PAI-1 induced by
plasminogen (or by plasminogen-derived
plasmin) did not inhibit plasminogen-induced MMP
activation, probably because sufficient plasmin was already generated
to activate MMPs.
The level of matrix-bound PAI-1 may respond to stimuli differently from PAI-1 in the media. Functionally, matrix-bound PAI-1 is more stable and active.10 In the present study, only the free forms were assayed. A comparison of the levels of free and bound forms might provide more insight into their relative importance in matrix remodeling. Furthermore, changes in plasminogen activator levels may be occurring in parallel with changes in PAI-1 levels. Thus, although circumstantial evidence indicates that PAI-1 is inhibiting plasminogen activation, other plasminogen activator inhibitors synthesized by vascular SMCs such as PAI-2 and protease–nexin I28 may play significant roles as well.
The data of the present study are consistent with the hypothesis that induction and activation of MMPs by plasminogen are consequences of plasmin activity. The ability of aprotinin to inhibit plasminogen-induced MMP activation provides further evidence for the role of plasmin. However, aprotinin inhibits a wide variety of serine proteases; therefore, it is possible that its effects on MMP activation are via a different pathway. Similarly, the unexpected induction of latent MMPs by aprotinin in control experiments may be an indirect consequence of its inhibition of endogenous active serine proteases.
A direct plasmin-independent effect of plasminogen has not been excluded by these studies. Treatment of SMC cultures with kringle 4, a lysine-binding fragment of plasminogen,29 did not affect MMP levels, but the results of treatment with kringle 1-3, another lysine-binding fragment,29 were inconclusive. Kringle 5, which has a non–lysine-binding site, is the main site of interaction of plasminogen with cultured human umbilical vein endothelial cells30 and may play a role in interactions of plasminogen with receptors on SMCs. The effects of kringle 5 were not explored in the present study.
Plasmin can directly degrade many extracellular matrix molecules, including fibronectin, laminin, and proteoglycans.31 In addition, plasmin can regulate matrix degradation by increasing the secretion and activation of MMPs. Degradation of matrix may cause changes in cell-matrix interactions, changes in the local stresses on cells, and changes in cell shape. These changes could then signal the cell to express proteins that are necessary for remodeling, including MMPs and PAI-1. For example, fibroblasts express collagenase and stromelysin in response to agents that cause loss of stress fibers.32 In addition, Werb et al33 found that fibronectin fragments but not native fibronectin induced collagenase and stromelysin gene expression in the absence of obvious changes in cell shape, indicating that fibronectin degradation stimulates remodeling activity. Thus, it is possible that both matrix-receptor mechanisms and cytoskeletal changes may explain the induction of PAI-1 by plasminogen.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by a grant from the American Heart Association (Massachusetts affiliate) and by a Merit Award from the Department of Veterans Affairs Research Service (Dr Vaughan). Dr E. Lee was supported by a Department of Defense National Science and Engineering Graduate fellowship. We thank Dr Marysia Muszynski for her excellent assistance with the Limulus amebocyte lysate test.
Received January 25, 1995; accepted September 11, 1995.
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A. Cho, J. Graves, and M. A. Reidy Mitogen-Activated Protein Kinases Mediate Matrix Metalloproteinase-9 Expression in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2527 - 2532. [Abstract] [Full Text] [PDF]
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T. Uchiyama, M. Kurabayashi, Y. Ohyama, T. Utsugi, N. Akuzawa, M. Sato, S. Tomono, S. Kawazu, and R. Nagai Hypoxia Induces Transcription of the Plasminogen Activator Inhibitor-1 Gene Through Genistein-Sensitive Tyrosine Kinase Pathways in Vascular Endothelial Cells Arterioscler Thromb Vasc Biol, April 1, 2000; 20(4): 1155 - 1161. [Abstract] [Full Text] [PDF]
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S. Lopez, F. Peiretti, B. Bonardo, I. Juhan-Vague, and G. Nalbone Tumor Necrosis Factor alpha Up-regulates in an Autocrine Manner the Synthesis of Plasminogen Activator Inhibitor Type-1 during Induction of Monocytic Differentiation of Human HL-60 Leukemia Cells J. Biol. Chem., February 4, 2000; 275(5): 3081 - 3087. [Abstract] [Full Text] [PDF]
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L. D. Adams, J. M. Lemire, and S. M. Schwartz A Systematic Analysis of 40 Random Genes in Cultured Vascular Smooth Muscle Subtypes Reveals a Heterogeneity of Gene Expression and Identifies the Tight Junction Gene Zonula Occludens 2 as a Marker of Epithelioid "Pup" Smooth Muscle Cells and a Participant in Carotid Neointimal Formation Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2600 - 2608. [Abstract] [Full Text] [PDF]
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F. G. Spinale, M. L. Coker, S. R. Krombach, R. Mukherjee, H. Hallak, W. V. Houck, M. J. Clair, S. B. Kribbs, L. L. Johnson, J. T. Peterson, et al. Matrix Metalloproteinase Inhibition During the Development of Congestive Heart Failure : Effects on Left Ventricular Dimensions and Function Circ. Res., August 20, 1999; 85(4): 364 - 376. [Abstract] [Full Text] [PDF]
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J. L. Bouchie, H. Hansen, and E. P. Feener Natriuretic Factors and Nitric Oxide Suppress Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells : Role of cGMP in the Regulation of the Plasminogen System Arterioscler Thromb Vasc Biol, November 1, 1998; 18(11): 1771 - 1779. [Abstract] [Full Text] [PDF]
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F. G. Spinale, M. L. Coker, C. V. Thomas, J. D. Walker, R. Mukherjee, and L. Hebbar Time-Dependent Changes in Matrix Metalloproteinase Activity and Expression During the Progression of Congestive Heart Failure : Relation to Ventricular and Myocyte Function Circ. Res., March 9, 1998; 82(4): 482 - 495. [Abstract] [Full Text] [PDF]
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D. Kessler, S. Dethlefsen, I. Haase, M. Plomann, F. Hirche, T. Krieg, and B. Eckes Fibroblasts in Mechanically Stressed Collagen Lattices Assume a "Synthetic" Phenotype J. Biol. Chem., September 21, 2001; 276(39): 36575 - 36585. [Abstract] [Full Text] [PDF]
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