Original Contributions |
From the Institute of Pharmacological Sciences, University of Milan (S.B., M.C., R.F., R.P.) and the Institute of Pharmacology and Pharmacognosy, University of Parma (F.B.), Italy; Baylor College of Medicine (D.V.), Houston, Tex; and Novartis Pharma AG (P.P.), Basel, Switzerland.
Correspondence to Prof Franco Bernini, Institute of Pharmacology and Pharmacognosy, University of Parma, Via delle Scienze, 43100 Parma, Italy. E-mail fbernini{at}ipruniv.cce.unipr.it
| Abstract |
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30%) in human monocytederived
macrophages as well. Phorbol esters (TPA, 50 ng/mL) stimulated
MMP-9 activity by 50%, and fluvastatin inhibited this
enhanced activity up to 50% in both mouse and human
macrophages. The above results on the secretion of MMP-9 were
confirmed by Western blotting and ELISA. The inhibitory
effect of fluvastatin was overcome by the
simultaneous addition of exogenous mevalonate (100
µmol/L), a precursor of isoprenoids. Fluvastatin's
effect was fully reversible, and the drug did not cause any cellular
toxicity. The statin did not block directly the in vitro activation of
the secreted protease. Similar data were obtained with simvastatin.
Altogether, our data indicate an inhibition of MMP-9 secretion by the
drug. This effect is mediated by the inhibition of synthesis of
mevalonate, a precursor of numerous derivatives essential for several
cellular functions.
Key Words: statins macrophages plaque stability metalloproteinases
| Introduction |
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Disrupted aortic caps contain fewer SMCs (collagen-synthesizing cells)
and less collagen than intact caps.3 5 Collagen
is the main component of fibrous caps responsible for their tensile
strength.5 In addition to the plaque rupture, the
matrix composition participates in several key events in the
development of the atherosclerotic lesion: cell migration and
proliferation, lipoprotein retention, cell adhesion, calcification,
thrombosis, coagulation, and apoptosis.6
A wide range of proteases may be produced at focal sites in plaques.
Macrophages are capable of degrading extracellular matrix by
phagocytosis or by secreting proteolytic enzymes, in particular a
family of metalloproteinases (MMPs) that may weaken the fibrous cap,
predisposing its rupture.7 The 92-kDa gelatinase
B, or MMP-9, is the most prevalent form, expressed by virtually all
activated macrophages, and has been shown to be more
common in atherectomy materials from unstable
angina8 and abdominal aortic
aneurysm.9 In addition to
macrophages, SMCs may release MMPs, an event relevant not only
to atherogenesis but especially to the process of restenosis
after angioplasty.7 MMPs play a major role in
restenosis by liberating the SMC from its pericellular matrix
cage as a prerequisite to proliferation and
migration.10 11 12 13 14 MMPs are a family of
Zn2+- and Ca2+-dependent
enzymes, which are important in the resorption of extracellular
matrixes in both physiological and pathological
processes. The MMPs are secreted as the proenzyme and, once
activated, can completely degrade all extracellular matrix
components. The regulation of these enzymes is very important and
occurs at 3 levels: transcription, activation of latent
proenzymes, and inhibition of proteolytic
activity.15 16 Interleukin-1,
platelet-derived growth factor, and tumor necrosis factor-
stimulate the synthesis of MMPs; transforming growth factor-ß
(TGF-ß), heparin, and corticosteroids have an
inhibitory effect.7 15 Plasmin is a
potent proenzyme activator of most MMPs, but
plasmin-independent pathways also exist.17 18 In
vitro experiments have shown that phorbol esters
(12-0-tetradecanoylphorbol 13-acetate [TPA]) and
lipopolysaccharide can stimulate MMP
secretion.19 MMPs are inhibited by a family of
naturally occurring specific inhibitors (tissue
inhibitors of metalloproteinases [TIMPs]), which are
secreted multifunctional proteins essential in the regulation of
connective tissue metabolism.
In addition to lipid-lowering therapy, which most probably affects the size of the atheromatous core, plaque stabilization could be achieved by a direct inhibition of MMPs in the arterial wall. Along with TGF-ß, corticosteroids, and heparin, several synthetic inhibitors have been investigated: namely, tetracyclines, antracyclines, and synthetic peptides. The efficacy of these molecules in therapy, however, is questionable.7 The inhibition of MMP activity also has been investigated in tumor therapy.
In our laboratory, we demonstrated that fluvastatin, a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin), may directly interfere with the major processes of atherogenesis occurring in the arterial wall.20 SMC migration and proliferation are inhibited by the drug,21 22 and cholesterol accumulation is prevented in macrophages23 by reducing modified-LDL endocytosis.24 Interestingly, the inhibitory activity observed in macrophages was more pronounced in cholesterol-loaded cells than in normal cells, suggesting a potential selectivity of the drug for the foam cells and hence for the atherosclerotic lesion.24 All cellular effects mentioned above are mediated by inhibition of the isoprenoid pathway. Because the isoprenoid pathway is involved in several cellular processes25 and macrophage-derived foam cells constitutively produce MMPs,26 we studied the effect of fluvastatin on secreted MMP-9 activity in macrophages in vitro.
| Methods |
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Circulating human monocytederived macrophages (HMs) were isolated from the blood of healthy donors. In brief, blood was centrifuged, and the buffy coats were underlayered with Ficoll-Paque (Pharmacia) and centrifuged at 320g for 35 minutes at 25°C. The monocytes in a broad band below the interface were collected using a siliconized Pasteur pipette and washed 3 times with cold PBS. The final pellet was resuspended in serum-free DMEM, and the cells were plated at a density of 3x106 cells in a 35-mm dish. After 2 hours, cell monolayers were washed twice, and the adherent cells were incubated for 10 to 14 days with DMEM containing 10% human AB serum and insulin (8 µg/mL).
To generate the conditioned media, cells were incubated for 24 hours at 37°C with DMEM supplemented with 0.2% BSA (Sigma) and increasing concentrations of fluvastatin in the absence or presence of phorbol esters (TPA, 50 ng/mL; Sigma). At the end of the incubation, the conditioned media were collected, and the activity of secreted MMP-9 was analyzed by zymography. Cellular protein content was measured according to Lowry et al.26 Cellular toxicity caused by the drug was assessed using the dimethylthiazaol-diphenyltetrazolium bromide assay (MTT), which relied on the ability of viable cells to actively metabolize a tetrazolium dye.27
SDSPolyacrylamide Gel Electrophoresis Zymography
Electrophoresis was performed on samples (40 µL for MPMs and 5
µL for HMs of conditioned medium per lane) at 4°C on 7.5%
polyacrylamide gels containing 10% SDS and gelatin (1 mg/mL)
under nonreducing conditions and without boiling. After
electrophoresis, SDS was removed from gels in 2 washes with 2.5%
Triton X-100 (Sigma) at room temperature. After washes, the gels were
incubated overnight at 37°C with gentle shaking in Tris (50
mmol/L; pH 7.5) containing NaCl (150 mmol/L),
CaCl2 (10 mmol/L), and
ZnCl2 (1 µmol/L) to activate the
MMP's ability to digest the substrate. For inhibition studies and to
confirm the identity of MMPs, identical gels were incubated in the
above buffer containing either EDTA (20 mmol/L), an
inhibitor of MMPs, or PMSF (1 mmol/L), an
inhibitor of serine proteinases. The addition of PMSF did
not alter MMP-9 activity, whereas the treatment with EDTA completely
abolished it (data not shown). At the end of the incubation, the gels
were stained with a solution of 0.1% Coomassie brilliant blue R-250
(Sigma) in 25% methanol and 7% acetic acid. Clear zones against the
blue background indicated the presence of proteinolytic activity. It is
important to note that in this SDS-containing gel, the latent form of
MMP-9, proMMP-9, and the activated gelatinase develop
gelatinolytic activity.28
Therefore, we used the word "activity" to indicate the total
gelatinolytic capacity measured in the conditioned
media, which, in our experimental conditions, is due entirely to the
92-kDa proMMP-9, as assessed by zymography and Western blot
analysis (see experimental data), and after activation by
incubation for 2 hours at 37°C with 2 mmol/L APMA
(4-aminophenylmercuric acetate), the propeptide is cleaved to the
active form (<90-kDa; data not shown).
Western Blot Analysis
Aliquots of the conditioned media (40 µL per lane) were run on
10% polyacrylamide gel containing SDS, under nonreducing
conditions. The proteins were blotted to nitrocellulose membranes
(Bio-Rad) and incubated with a 3% solution of defatted dried milk in
PBS containing 0.1% Tween 20 (PBS-T) to block nonspecific binding.
Then a mouse monoclonal antibody antihuman MMP-9 (clone 6-6B;
Calbiochem) diluted in PBS-T was added, and the incubation continued
for 1 hour. This antibody recognizes both the latent (92 kDa) and
active (83 kDa) forms of human MMPs-9 under nonreducing conditions but
only the latent form under reducing conditions.29
The bound primary antibody was detected using an anti-mouse secondary
antibody conjugated to horseradish peroxidase (Sigma) and the enhanced
chemiluminescence kit (Amersham) according to the manufacturer's
instructions.
Northern Blot Analysis
RNA was extracted (RNAzol B; Tel-Test Inc) from
3x107 to 4x107 primary
HMs cultured for 12 days and treated with and without 50 µmol/L
fluvastatin for 24 hours before harvest. Equal amounts of
total RNA (10 µg) were denatured in 2.2 mol/L formaldehyde, 50%
deionized formamide, and 50 mmol/L MOPS (pH 7.0) at 55°C and
electrophoresed on 1% agarose gels containing 3.4% formaldehyde. RNA
was blot-transferred to GeneScreen Plus membranes using 10x SSC and
fixed with UV irradiation. Blots were prehybridized at 68°C for 1
hour. An MMP-9 probe was generated from THP-1 cells treated with TPA by
reverse transcriptionpolymerase chain reaction (PCR) of total RNA
using the following primers: sense, 5' TGGGCAGATTCCAAACCTTTGAGGGC 3'
and antisense, 5' CCATTCACGTCGTCCTTATGCAAGGG 3'. The 1003-bp
product was subcloned into the pCRII vector, and its sequence was
verified as MMP-9. Purified MMP-9 probe (QIAquick, Quiagen, 25 ng)
generated by PCR from the vector or a G3PDH probe (Clontech) were
labeled with [32P]dCTP by random priming and
incubated with the blots in ExpressHyb (Clontech) for 1 hour at 68°C.
Blots were washed (2x SSC; 0.05% SDS) exhaustively at room
temperature and given a final wash at 50°C (0.1x SSC; 0.1% SDS) for
10 minutes. Blots were exposed for autoradiography
(X-OMAT AR, Kodak) and then placed on a Bio-Rad BI screen for
quantitative analysis in the Bio-Rad GS 363 Molecular Imager.
After autoradiography to detect MMP-9 mRNA, the blot
was stripped by incubation in 0.01% SDS, 0.01x SSC for 15 minutes at
100°C. The blot then was reprobed for the G3PDH housekeeping
gene.
ELISA
The amount of secreted MMP-9 protein was quantified using the
highly specific Biotrak Matrix MMP-9 ELISA systems (Amersham). The
MMP-9 assay uses 2 antibodies directed against different epitopes of
MMP-9 and does not show detectable cross-reactivity with MMP-1, -2, and
-3 and TIMP-1 and -2 (Amersham). Aliquots of conditioned media were
analyzed as suggested by the manufacturer.
Statistical Analysis
For quantitation of Western blots and zymograms, densitometric
scanning was performed using a system incorporating a video camera and
a computer analysis package (NIH Image 1.52 image
analysis software). Each experiment was performed at least 3
times with different preparations of cells. Background was set for each
gel, and each lane was analyzed sequentially. Results were
normalized by cellular protein content and expressed as optical density
units. To validate the method, a linear response of optical density
units versus dilution was obtained for different serial dilutions on 2
separate samples (data not shown). To standardize conditions between
gels, an aliquot of a standard sample was loaded on each gel, and
values for each band then were normalized to the value of the band of
the reference sample run on the same gel. Data are presented as
mean±SD and analyzed using the Student t test. P
values <0.05 were considered statistically significant
| Results |
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Our previous data have shown that fluvastatin may directly
interfere with the major processes of atherogenesis occurring in the
arterial wall20 through the
inhibition of the isoprenoid pathway. Because mevalonate is the
precursor of isoprenic compounds, we postulated that the
inhibitory effect of fluvastatin might be due
to a deprivation of mevalonate caused by the drug. To test
this hypothesis, we incubated the cells with fluvastatin in
the presence of exogenous mevalonate (100 µmol/L). As shown in
Figure 3
, the addition of mevalonate
fully overcame the inhibitory effect of the statin, in both
the absence and presence of TPA.
|
To determine whether the inhibitory effect of fluvastatin was due to an interference with the activation process after MMP-9 had been secreted, we incubated MPMs with medium alone. After 24 hours, the conditioned media were collected, divided in aliquots, and added with increasing concentrations of the tested drugs. Media then were incubated for 24 more hours at 37°C, in the absence of cells, and analyzed by gelatin gel zymography. None of the tested compounds showed any appreciable effect on MMP-9 activity (data not shown), thus suggesting that fluvastatin did not interfere with the activation of the protease.
To exclude a possible drug toxicity as the reason of its
inhibitory effect, MPMs were incubated with
fluvastatin (5 to 100 µmol/L) in the absence or
presence of TPA (50 ng/mL); then, cell viability was assessed using the
dimethylthiazaol-diphenyltetrazolium bromide assay.
Fluvastatin did not cause any appreciable cellular
toxicity, even at the highest concentration used (100 µmol/L).
In another set of experiments, cells were incubated for 24 hours with
medium containing fluvastatin and then for 24 hours with
medium alone. As shown in Table 1
,
withdrawal of the drug restored the capacity of cells to secrete normal
amounts of MMP-9. These data further confirm that
fluvastatin is not toxic and that its
inhibitory effect is reversible.
|
To assess whether fluvastatin was effective also in HMs, we
performed a new series of experiments. As shown in Figure 4A
, the incubation of HMs with increasing
concentrations of fluvastatin caused a significant and
dose-dependent reduction of MMP-9 activity in the culture medium. At
the lowest concentration used (0.1 µmol/L),
fluvastatin inhibited MMP-9 activity by 20%, and at the
highest (50 µmol/L), by 45% compared with control (Figure 4A
).
Fluvastatin inhibitory effect was also
maintained in the presence of phorbol ester. The addition of TPA alone
(50 ng/mL of medium) determined a 2.5-fold increase of MMP-9 activity
(Figure 4B
). This enhancement was dose-dependently blocked (25%
to
60% compared with cells treated with TPA alone) by increasing
amounts of fluvastatin (0.1 to 50 µmol/L; Figure 4B
).
|
We also performed a Western blot analysis of the media
collected from HMs incubated with fluvastatin. As shown in
Figure 5
, the addition of
fluvastatin, 5 and 50 µmol/L, reduced the amount of
MMP-9 protein released into the incubation media by 25% and 50%,
respectively. The coincubation with exogenous mevalonate blocked the
inhibitory effect of fluvastatin (Figure 5
).
|
To confirm the above observation obtained with murine
macrophages that the inhibitory effect of
fluvastatin was not due to an interaction of the drug with
the protease already secreted into the media, we performed a different
experiment. HMs were incubated with fluvastatin (5
µmol/L alone or with 100 µmol/L mevalonate) for 24 hours.
Media were discarded, and cells were incubated for an additional 4
hours with medium alone. At the end of the second incubation, media
were collected and analyzed by zymography.
Fluvastatin still maintained its inhibitory
effect on MMP-9 activity, and mevalonate prevented this effect (Figure 6A
). This reduction in
gelatinolytic activity is due to a reduction of the
amount of MMP-9 protein released in the incubation media, as shown by
Western blot analysis (Figure 6B
).
|
We also measured the amount of MMP-9 protein secreted by HMs with
ELISA. As shown in Table 2
, the addition
of fluvastatin (5 and 50 µmol/L) inhibited the
secretion of MMP-9 protein, whereas the coincubation with mevalonate
prevented the inhibitory effect.
|
To determine whether the inhibitory effect we observed was
specific to fluvastatin, we used a different HMG-CoA
reductase inhibitor simvastatin. Data in Table 3
show that the incubation of mouse
macrophages with increasing concentrations of the latter statin
caused an inhibition in MMP-9 activity similar to that observed with
fluvastatin.
|
Finally, we evaluated by Northern blot analysis whether the
reduced levels of secreted MMP-9 in fluvastatin-treated HMs
could reflect a reduction in MMP-9 gene expression. As shown in Figure 7
, Northern blots of HMs treated for 24
hours with 50 µmol/L fluvastatin demonstrated no
reduction in the level of MMP-9 gene expression. Instead, an almost
2-fold increase in mRNA levels for MMP-9 was consistently
observed. In contrast, essentially no change was observed in the levels
of the housekeeping gene G3PDH.
|
| Discussion |
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The inhibitory effect of fluvastatin on MMP-9 activity detected by zymography could be the consequence of direct interference of the drug with the activation process of the MMPs after this has been secreted. Our data exclude this hypothesis, because the drug did not have any effect on the activity of MMP-9 already secreted into the growth media. In addition, as evaluated by Western blot analysis and ELISA, fluvastatin reduced the amount of MMP-9 protein released by the cells, suggesting a direct effect on the secretion process.
The reduced levels of MMP-9 detected in the media by ELISA, Western blot analysis, and zymography could also be the result of a fluvastatin-mediated decrease in MMP-9 gene expression. Our data clearly indicate that this is not the case, because mRNA levels actually rose in treated cells. This would suggest a complex mechanism of action of the drug affecting posttranscriptional processes for MMP-9. A more detailed examination of these processes, beyond the scope of this article, will be required to fully understand the mechanism(s) involved.
In addition to TGF-ß, corticosteroids, and heparin, several synthetic inhibitors of MMPs have been investigated: viz, tetracyclines, antracyclines, and synthetic peptides. The therapeutic efficacy of all of these molecules, however, is doubtful.7 Inhibition of MMP activity has demonstrated a direct effect in reducing tumor cells invasion and angiogenesis.30 31 32 The MMP inhibitor GM 6001 was shown to block SMC migration.33 The synthetic MMP inhibitor BB94 (Batimastat) inhibits gelatinases A and B with IC50 values of 4 and 10 nmol/L, respectively,34 and is able to reduce intimal thickening after arterial injury by decreasing both SMC migration and proliferation.35 These data support the conclusion that MMPs play a significant role in regulating intimal thickening in injured arteries and therefore in atherogenesis.
Fluvastatin and simvastatin are inhibitors of the HMG-CoA reductase enzyme, a key step in the cholesterol biosynthetic pathway, which synthesizes mevalonate, the precursor of isoprenoids, a class of compounds involved in several cellular processes. The treatment with the inhibitors causes mevalonate starvation inside the cells. This seems to cause the inhibition of MMP-9 secretion, because the coincubation with mevalonate completely overcame the reduction of MMP-9 secretion. Prenylation is a type of stable lipid modification involving covalent addition of either farnesyl or geranylgeranyl isoprenoids to conserved cysteine residues at or near the C-terminus of proteins.36 Known prenylated proteins include fungal mating factors, nuclear lamins, Ras and Ras-related GTP-binding proteins, protein kinases, and at least 1 viral protein.36 Prenylation promotes membrane interactions of most of these proteins and plays a major role in several protein-protein interactions and in signal transduction.36 Prenylated proteins of the Rab subgroup, small Ras-like GTPases in mammalian cells, have an important role in regulating membrane traffic and exocytic and endocytic transport processes.37 An inhibition of Rab prenylation causes a block in protein secretion,38 and the Rab3A is deeply involved in regulated secretion in neuronal cells.36 Therefore, it is conceivable that the inhibition of isoprenoids formation by statins could lead to a reduced MMP-9 secretion by macrophages, by inhibiting factor(s) essential for the secretion process.
Extrapolation of our in vitro results to the in vivo condition is difficult, of course. The final net level of proteinase activity depends on several factors, such as the relative concentrations of active enzymes and specific inhibitors (ie, TIMPs), and further studies are required to assess the in vivo relevance of our observation. Nevertheless, several clinical studies demonstrated the ability of statins to reduce the incidence of coronary heart disease,39 40 most probably by increasing the stability of the atherosclerotic plaque rather than by reducing the stenotic occlusion.2 This effect may involve, in addition to cholesterol reduction, a direct effect of these drugs on the arterial wall. We previously suggested that statins may reduce modified LDL endocytosis and cholesterol accumulation in macrophages.24 The inhibitory effect of statins on MMP-9 secretion observed in the present study suggests an additional potential mechanism for the stabilizing effect of these drugs on atherosclerotic plaque.41
| Acknowledgments |
|---|
Received August 8, 1997; accepted April 17, 1998.
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