Original Contributions |
From INSERM U 426 and the Department of Physiology, Faculté de Médecine Xavier Bichat, Université Denis Diderot (M.E., D.P., B.E., G.F.), and INSERM U 64, Hopital Tenon (G.N., J.-D.S.), Paris, France.
Correspondence to Dr Marie Essig, INSERM U 426, Faculté de Médecine Xavier Bichat, 16, rue Henri Huchard, F-75018, Paris, France. E-mail essig{at}bichat.inserm.fr
| Abstract |
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-hydroxyfarnesyl phosphonic acid, an
inhibitor of protein farnesyl transferase. C3 exoenzyme, an
inhibitor of the geranylgeranylated-activated Rho
protein, reproduced the effect of lovastatin on tPA and
plasminogen activator inhibitor-1
activity and blocked its reversal by geranylgeranyl pyrophosphate. The
effect of HRI was associated with a disruption of cellular actin
filaments without modification of microtubules. A disrupter of actin
filaments, cytochalasin D, induced the same effect as
lovastatin on tPA, whereas a disrupter of microtubules,
nocodazole, did not. In conclusion, HRI can modify the fibrinolytic
potential of endothelial cells, likely via inhibition
of geranylgeranylated Rho protein and disruption of the actin
filaments. The resulting increase of fibrinolytic activity of
endothelial cells may contribute to the beneficial
effects of HRI in the progression of atherosclerosis.
Key Words: atherosclerosis plasminogen activator isoprenoid Rho protein endothelium
| Introduction |
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HRIs were designed to inhibit the endogenous synthesis of cholesterol, thereby decreasing LDL synthesis in liver, thus leading to a reduction of lipid deposition in arteries and to a delayed growth of atherosclerotic plaques. However, some studies raised the question of the exclusive involvement of the decrease in plasma LDL concentration on the effects of HRIs. Indeed, HRIs induced clinical benefits before any regression in atherosclerotic plaques could be detected,5 they diminished cardiovascular mortality even in normocholesterolemic or hypocholesterolemic patients,3 and their effects were different from those observed after reduction of plasma cholesterol levels by surgical therapy.6 All these results suggest that the clinical benefit of HRI administration may result from multiple effects on the components of the atherosclerotic lesions. Atherosclerosis and vascular thrombosis result from complex changes and interactions between blood vessels and blood constituents, of which, fibrin deposition and fibrin lysis are major factors.7 Fibrinolysis results from the cleavage of fibrin by plasmin, a serine protease that is activated by the plasminogen activators (PAs).8 Two physiological PAs have been described, tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). In turn, tPA and uPA activity are tightly regulated by a specific inhibitor, plasminogen activator inhibitor-1 (PAI-1).
Abnormalities such as high fibrinogen levels9 or high PAI-1 and low tPA levels10 have been described in patients with hyperlipoproteinemia. Lipoprotein(a), which reduces tPA-mediated clot lysis,11 and PAI-1 have also been shown to be an independent risk factor for myocardial infarction.12
In vivo studies of the effect of HRIs on fibrinolysis, in animals or in humans, led to conflicting results on tPA activity,13 14 15 and these discrepant results may be explained by a rapid clearance of PAs and PA/PAI-1 complexes by receptor-mediated endocytosis in the liver.16 Thus, analysis of plasma tPA and/or PAI-1 activity may not reflect the local modification of the fibrinolytic system, which could regulate the atherosclerotic process.
Since the local fibrinolytic activity in blood vessels is determined to a large extent by the endothelial cell production of tPA and PAI-1,17 we investigated the effect of HRI on the balance between tPA and PAI-1. We show that HRIs induce an increase of tPA synthesis and release and a decrease in PAI-1 activity. The resulting increase in local fibrinolytic activity may explain the beneficial effects observed with HRIs on atherosclerosis progression.
| Materials and Methods |
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-tubulin, FITC-conjugated secondary antibody,
TRITC-phalloidin, bovine fibrinogen, and bovine thrombin were purchased
from Sigma Chemical Co.
-Hydroxyfarnesyl phosphonic acid (HFPA) was
from Calbiochem. Agarose was from Eurobio. Anti-human uterine tPA and
anti-human PAI-1 were from Biopool. SDS and 30%
acrylamide/Bis (37:1 and 5:1) solutions were from Bio-Rad.
Murine tPA cDNA was a gift from R. Lijnen (Leuven, Belgium). Human
PAI-1 cDNA was from D.J. Loskutoff (La Jolla,
Calif).18 Recombinant C3 exoenzyme was a kind
gift from M.R. Popoff (Institut Pasteur, Paris, France). Culture media
and reagents were from GIBCO-BRL. Plasticware was from Costar. The molecule of lovastatin was converted to its active form as described by Kita et al.19 To produce the mevalonate salt, 13 mg of mevalonic acid lactone was incubated in 0.1N NaOH (2 hours, 50°C, pH 7.4); the 0.1 mol/L stock solution was stored at -20°C.
Animal Experiments
Male Wistar rats (Iffa Credo) (160 to 180 g) received
once-daily subcutaneous injections of either lovastatin at
a dose of 4 mg/kg body wt or the propylene glycol/ethanol (vol/vol)
vehicle. Animals were treated for 2 days before they were killed
and the aortas were isolated. Blood samples were collected before the
animals were killed for study for determination of plasma
cholesterol. Each group contained 3 animals.
After isolation, aortas were abundantly rinsed, lysed in a 0.25% Triton X-100/0.1 mol/L Tris HCl (pH 8.1) solution as described by Huarte et al,20 and centrifuged 5 minutes at 14 000g. Supernatants of the lysates were collected and frozen at -20°C until analysis for tPA activity.
Cell Culture
Simian virus 40transformed rat aortic
endothelial cells (SVARECs) were a gift from Dr J.-B.
Michel (INSERM U 460, Paris, France). Cells were derived from
Sprague-Dawley rats as described previously in
detail.21 Endothelial cell clones
were identified by their typical cobblestone appearance, their capacity
to metabolize acetylated LDL, and their positive staining for
the von Willebrand factor. The cells were cultured in a medium
containing 5% FCS. For experiments, cells were deprived of FCS for 12
hours and then incubated with lovastatin or others drugs in
the absence of FCS. At the end of the incubation period, cells
supernatants were collected, centrifuged (15 minutes,
14 000g, 4°C), and frozen at -20°C until
analysis. Human umbilical vein endothelial
cells (HUVECs) were isolated and cultured, as previously described by
Jaffe et al,22 in culture medium supplemented
with 20% FCS. For experiments, cells were incubated in culture medium
containing 1% FCS for 36 hours.
Quantification of tPA
tPA activity present in SVAREC supernatants was quantified
by using a chromogenic assay (Spectrolyse/Fibrin, Biopool).
Samples were diluted (1:40) and analyzed as described by
the manufacturer. To minimize the differences between animals or HUVEC
cell numbers, tPA activity in aortic lysates or in HUVEC supernatants
was related to protein content of aortic or HUVEC cell lysates.
Statistical analyses of the data were performed using 1-way ANOVA followed by a protected least significant difference test. Statistical significance was accepted at P<0.05.
Zymographies
Zymographies were performed on SVAREC supernatants. One
microgram of total proteins was mixed with the gel electrophoresis
buffer. After separation on 10% SDS-PAGE, the gel was soaked in Triton
X-100 (2.5%) for 1 hour and layered onto a fibrin agarose gel
containing bovine plasminogenenriched fibrinogen (7
mg/mL), bovine thrombin (40 U/mL), and agarose (1%), as previously
described by Loskutoff and Schleef.23 Zymograms
were allowed to develop for 12 to 48 hours at 37°C.
Plasminogen activator inhibitor
activity was detected by reverse fibrin zymography with the addition of
uPA (final concentration, 0.5 U/mL) to the fibrin agarose
underlay.
Photographs of the gel were scanned by an imaging densitometer and quantified using the NIH Image 1.55 software program. Data are expressed as the mean±SEM in arbitrary units.
Immunoblotting
Immunoblotting of samples obtained from 10-fold
concentrated supernatants was carried out by standard techniques.
Twenty micrograms of total proteins was mixed with the gel
electrophoresis buffer and separated on 10% SDS-PAGE under nonreducing
conditions. The proteins were transferred to a nitrocellulose membrane
(Bio-Rad). A 10% solution of nonfat dried milk in PBS containing 0.1%
Tween 20 (PBST) was used to block nonspecific binding and to dilute the
primary and the secondary antibodies. The primary antibody was a
polyclonal goat anti-human tPA IgG and a polyclonal goat anti-human
PAI-1 (diluted 1:500). After blocking for 1 hour at 37°C, the
membrane was incubated for 1 hour at 37°C with the primary antibody,
and then the membrane was washed 3 times with PBST, incubated for 1
hour at 37°C with horseradish peroxidaseconjugated secondary
antibody (Jackson Immunoresearch Laboratory), and washed 6 times
with PBST. Immunoreactive protein bands were detected by the enhanced
chemiluminescence method (ECL kit, Amersham).
Protein concentrations were determined by the method of Bradford using the Coomassie protein assay reagent from Pierce.
RNA Isolation and Analysis
RNA was isolated from SVARECs as previously described by
Chomczynski and Sacchi.24 Twenty micrograms of
total RNA was electrophoresed in 1% agarose denaturing gels containing
formaldehyde and transferred overnight to nylon membranes (Hybond N,
Amersham). After cross-linking (2 hours at 80°C), membranes were
prehybridized for 4 hours at 42°C in hybridization buffer (50%
formamide, 6x SSC, 0.5% SDS, and 100 mg/mL salmon sperm DNA). The
murine tPA cDNA and the human PAI-1 cDNA were labeled with
[32P]dUTP by in vitro transcription, as
described by the manufacturer (Kit Riboprobe Gemini II, Promega), using
the T3 polymerase for the tPA cDNA and the T7 polymerase for the PAI-1
cDNA. The membranes were hybridized overnight at 42°C and washed
twice with 2x SSC and 0.1% SDS at 25°C and then with 0.1x SSC and
0.1% SDS at 60°C. Autoradiography was performed by
standard procedures using X-AR5 films (Kodak) and intensifying screens
at -80°C. Radioactivity was quantified using an Instantimager
(Packard).
Immunofluorescence
Cells, grown on glass coverslips, were fixed and stained after
24-hour incubation with cytochalasin D, nocodazole,
lovastatin, GGPP, or C3 exoenzyme. Cells were washed with
PBS, fixed in 4% formaldehyde/PBS for 10 minutes, and
permeabilized in Triton X-100 (0.1% in PBS) for 5
minutes at room temperature. Cells were incubated either with
TRITC-phalloidin (1:1000 in PBS) for 30 minutes at 37°C or with the
monoclonal antibody anti-human
-tubulin for 1 hour at 37°C (1:2000
in 1% PBS/BSA) revealed by an FITC-conjugated secondary antibody.
After 2 washes in PBS, coverslips were mounted using the Dako Faramount
mounting medium. Stained cells were stored in the dark at 4°C until
analysis with a Nikon microscope.
| Results |
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Isolated aortas showed a 3-fold increase in tPA activity compared with
aortas of vehicle-treated rats (0.35±0.05 versus 1.05±0.8 IU/mg
protein, P<0.002) (Figure 1
).
In contrast to tPA, no uPA activity could be detected in aortic
lysates.
|
Characterization of the Effects of Lovastatin on the
Fibrinolytic System of Endothelial Cells
To better characterize the effects of lovastatin on
the fibrinolytic activity of endothelial cells, we next
performed experiments on a rat aortic endothelial cell
line (SVARECs) and on human endothelial cells (HUVECs)
as controlled nontransformed cells. SVARECs, as nontransformed
endothelial cells, synthesized and released some PAs to
promote clot lysis. In SVAREC supernatants, only tPA was observed. No
uPA activity could be detected by zymography or by
immunoblot. The same pattern of activity was observed in
HUVEC supernatants. However, tPA activity was higher in SVAREC
supernatant than in HUVEC supernatant (2.88±0.22 versus 0.11±0.006
IU).
As described in other systems,17 tPA synthesis by SVARECs and HUVECs was affected by the presence of FCS in the medium. Since the effect of FCS could have masked the effects of the HRI, we performed all subsequent experiments on SVARECs after 12 hours of FCS deprivation, and the cells were incubated in medium without FCS. For HUVECs, which could not be serum-starved, we performed the experiments with 1% FCS, the lowest FCS concentration capable of maintaining the viability of HUVECs for 36 hours.
Lovastatin, added to the medium for 48 hours, induced a
dramatic increase in tPA activity that was detectable in SVAREC
supernatants (control, 2.88±0.22 IU; 25 µmol/L
lovastatin, 8.75±0.66 IU; P<0.001). This
effect on tPA secretion was observed in the 1- to 50-µmol/L range,
with a maximum at 50 µmol/L (Figure 2A
), and was reproduced by 2 other HRIs,
simvastatin and compactin, in the same range of
concentrations (Figure 2A
).
|
Studies performed on HUVECs showed that lovastatin
similarly increased tPA activity (control, 0.457±0.018 IU/mg protein;
5 µmol/L lovastatin, 1.29±0.117 IU/mg protein;
P<0.001). Furthermore, the effects were observed for
10-fold lower concentrations of lovastatin in HUVECs
compared with SVARECs (Figure 2B
).
Time-course studies showed that the increase of tPA due to
lovastatin was already detectable after a short incubation
time (3 hours) and increased in magnitude with the incubation time,
reaching a maximum after 48 hours of incubation (Figure 3
).
|
The increase in tPA activity induced by lovastatin was
attributed to an increase in protein expression and not to an increase
of tPA-specific activity, since it was accompanied by an increase of
tPA antigen visualized by immunoblot: a single band of 68
kDa was detected by immunoblot analysis in control
cells and increased in the presence of lovastatin (Figure 4A
). This increase was likely the
consequence of increased protein synthesis, inasmuch as tPA mRNA
content was induced 2.5-fold after 60 minutes of incubation with
lovastatin (25 µmol/L) (Figure 4B
).
|
PAI-1 secretion was also affected by lovastatin, which
induced a decrease in PAI-1 activity (Figure 5A
) and mRNA (Figure 5B
). Because of the
poor sensitivity of the method, we could not detect PAI-1 antigen by
immunoblot. The decrease in PAI-1 activity occurred for the
same concentration range of lovastatin. The concomitant
increase in tPA and decrease in PAI-1 activities is likely to be
synergistic with respect to the stimulation of the fibrinolytic system
by lovastatin.
|
Reversal of the Effects of Lovastatin by
Isoprenoids
The effects of lovastatin on tPA activity and protein
expression were completely reversed by mevalonate (500 µmol/L),
the synthesis of which is catalyzed by HMG CoA reductase, whereas LDL
cholesterol (50 µg/mL) did not (control, 3.49±0.06 IU;
lovastatin, 12.76±0.782 IU;
lovastatin+mevalonate, 3.53±0.53 IU; and
lovastatin+LDL cholesterol, 13.99±0.53 IU;
P<0.001). These results suggested that the effects of
lovastatin involved a modulation of the mevalonate pathway
but that end derivatives of the mevalonate pathway, such as
cholesterol, were not involved in tPA modulation.
Among the early derivatives synthesized along the mevalonate pathway,
the isoprenoids FPP and GGPP are involved in protein regulation by a
posttranslational modification leading to the adjunction of the
isoprenoids to the COOH terminal part of the protein. To determine
whether the effects of lovastatin were mediated by the
isoprenylation of a protein, we incubated cells in the presence of
lovastatin and of the 2 isoprenoids FPP and GGPP (Figure 6
). FPP and GGPP alone did not modify tPA
and PAI-1 activity (data not shown). FPP (15 µmol/L) did not
abolish tPA increase, and HFPA (15 µmol/L), a competitive
inhibitor of the farnesyl transferase, could not reproduce
the effects of lovastatin, suggesting that modulation of a
farnesylated protein was not involved in tPA regulation. In contrast
with FPP, GGPP (15 µmol/L) completely inhibited the augmentation
of tPA and the decrease of PAI-1 activity observed with
lovastatin (Figure 6A
). tPA protein increase was also
prevented by GGPP, as shown by the immunoblot
analysis (Figure 6C
), suggesting the involvement of a
geranylgeranylated protein in tPA regulation.
|
Interaction With Intracellular Signaling Pathways
Among the isoprenylated small GTP proteins, the Rho and the Rab
proteins are known to be mostly
geranylgeranylated.25 To determine whether the
effects of lovastatin on tPA activity may result from the
inhibition of Rho proteins, we incubated cells in the presence of C3
exoenzyme, a specific inhibitor of the Rho
proteins26 (Figure 7
). C3 exoenzyme (5 µg/mL) induced
the same effect as lovastatin on tPA and PAI-1 activity,
had no synergistic effects with FPP and lovastatin, and
blocked the reversal of the effects of lovastatin by GGPP,
suggesting the involvement of Rho proteins. The involvement of other
geranylgeranylated proteins different from Rho proteins seemed highly
improbable, since C3 exoenzyme completely prevented the effects of
GGPP, and GGPP did not modify the effects of C3 exoenzyme on tPA and
PAI-1 synthesis.
|
Modification of the Cytoskeleton
Since Rho proteins are known to regulate the cytoskeletal
proteins,27 we evaluated whether the modulation
of tPA activity could be accounted for by a modification of the
cytoskeleton. Cytochalasin D, a well-known disrupter of the actin
filaments, dose-dependently (20 nmol/L to 20 µmol/L) induced an
increase in tPA activity. This effect was correlated with the
progressive disappearance of the cellular actin stress fibers (Figure 8A
). In contrast, nocodazole, which
disrupts microtubules, had no effect on tPA activity and actin stress
fibers (Figure 8B
). Lovastatin (25 µmol/L) induced a
disruption of the cellular actin stress fibers compared with control
cells, without any modification of the microtubule network (Figure 9
). The correlation between the
organization of actin filaments and the level of tPA was also
reproduced with the GGPP, FPP, and C3 exoenzyme (data not shown). GGPP
completely prevented the disappearance of actin stress fibers induced
by lovastatin, whereas FPP did not. C3 exoenzyme induced
the same disruption of the cellular actin filaments as
lovastatin and blocked the reversal of the effect by GGPP.
These results may suggest that tPA activity was regulated by the
cytoarchitecture of the cells and that the induction of tPA synthesis
by lovastatin might result from modifications of the actin
filaments.
|
|
| Discussion |
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Although the concentration of lovastatin used in the present study was higher than that observed in the plasma of patients treated with lovastatin (0.01 to 0.5 µmol/L),28 the relevance of the effects observed in this study for patients treated with HRI was supported by several facts. First, the results were observed in vivo with doses of lovastatin previously reported in the treatment of hyperlipidemia in different models of hyperlipidemic rats.29 30 Second, the concentration of lovastatin needed to induce tPA activity in nontransformed human endothelial cells (HUVECs) was in the same range as that which inhibits the proliferation of smooth muscle cells,31 glomerular mesangial cells,32 and fibroblasts.33 In SVARECs, higher concentrations of HRIs were necessary to observe the same effects. It is likely that these differences could be accounted for by the higher HMG CoA reductase activity present in simian virus 40transformed cell lines, such as SVARECs, as demonstrated by Larsson.34
In contrast to the inhibitory effect of lovastatin on proliferation, which was observed after a long incubation period with the drug (24 and 48 hours), stimulation of fibrinolysis was detectable after treatment as short as 2 days and an incubation time of 3 hours.
The fact that simvastatin and compactin, 2 other HRIs, reproduced the effects of lovastatin indicated that the mechanism of the stimulation was related to the inhibition of the mevalonate pathway (which leads to the synthesis of cholesterol) and of a variety of isoprenoid metabolites: dolichol, ubiquinone, and the isoprenoids FPP and GGPP. The complete reversal by mevalonate of the action of lovastatin confirmed this hypothesis.
Since interactions between cholesterol, LDL cholesterol, and fibrinolysis have been suspected for a long time by epidemiological studies10 or by immunohistological and in situ hybridization analysis of atherosclerotic lesions,35 we first explored the modulation of fibrinolysis exerted by the exogenous precursor of cholesterol, LDL cholesterol. In the present study, incubation of SVARECs with LDL cholesterol did not induce any modification of tPA. Furthermore, LDL cholesterol did not prevent the increase in tPA activity induced by lovastatin. As demonstrated by Steinbrecher et al,36 LDL cholesterol is oxidized by endothelial cells to form oxidized LDL cholesterol. Our results suggested that oxidized LDL did not modulate fibrinolysis in SVARECs and that lovastatin action did not result from an inhibition of oxidized LDL. These results are in agreement with those of Latron et al,37 who did not find any modulation of tPA synthesis by native LDL or oxidized LDL. Results obtained in SVARECs suggest that lovastatin-induced modulation of tPA did not result from a decrease in endogenous cholesterol synthesis and raise the possibility that HRIs could prevent atherosclerosis even in normocholesterolemic patients.
Regarding other metabolites of the mevalonate pathway, we determined that lovastatin action was blocked by GGPP, whereas FPP had no effect. Furthermore, HFPA, a potent inhibitor of farnesyl transferase, did not reproduce lovastatin stimulation of tPA synthesis. FPP and GGPP have been implicated in protein isoprenylation, in the regulation of cell proliferation, and in signal transduction. Prenylated proteins share characteristic C-terminal sequences that determine which of the 2 isoprenoids, FPP or GGPP, is covalently linked to the protein. Since C-terminal sequences of tPA and PAI-1 do not possess such sequences, it is unlikely that these proteins are directly regulated by isoprenylation. The absence of reversal by FPP and the lack of effect of HFPA suggested that p21 ras, the major farnesylated protein that is inhibited by HRIs,38 is not involved in lovastatin action. Indeed, previous studies have rather demonstrated that p21 ras stimulated fibrinolysis.39 In contrast, reversal of the action of lovastatin by GGPP occurred at low concentrations of this metabolite (15 µmol/L) compared with the effective concentration of mevalonate (500 µmol/L), thus suggesting a specific involvement of a geranylgeranylated protein in fibrinolysis modulation. To our knowledge, the present study is the first to demonstrate a direct effect of geranylgeranylated proteins in the regulation of fibrinolysis of endothelial cells.
Among the geranylgeranylated proteins, the Rho family is one of the most important being implicated in various cell functions, such as cell morphology, cell motility, or cytokinesis. We demonstrated that the effect of lovastatin on tPA and PAI-1 was reproduced by the C3 exoenzyme, which inhibits Rho proteins by ADP-ribosylation on asparagine 41 in the effector region of the GTPase.40 Furthermore, we determined that C3 exoenzyme blocked the reversal of the effects of lovastatin induced by GGPP, thus suggesting the involvement of the Rho protein family in the action of lovastatin on fibrinolysis.
The mechanism linking Rho proteins to fibrinolysis is not fully elucidated. An involvement of the cytoskeleton is suspected, since Rho proteins are known to regulate the organization of the cytoskeleton and the formation of actin filaments.26 Along this line, Fenton et al41 and Bifulco et al42 demonstrated that HRIs could modify the cytoskeleton organization and the polymerization of intracellular actin. We confirmed on SVARECs that HRIs induced a disruption of the actin filament network without affecting the microtubules. This effect, which was reversed by GGPP, seemed to depend on activated Rho proteins, since it was blocked by C3 exoenzyme. The effects of HRIs on fibrinolysis, on the one hand, and on the disruption of the actin filaments through the inhibition of Rho proteins, on the other hand, are likely to be linked. Indeed, cytochalasin D, which is known to disrupt actin filaments,43 induced the same effect as lovastatin and C3 exoenzyme, whereas nocodazole, which disrupts the microtubules, did not. Along the same line, Snyder et al44 demonstrated a stimulation of tPA by dihydrocytochalasin B in F9 teratocarcinoma cells. Moreover, the extensively studied link between cytoskeleton and urokinase45 46 47 suggests that modulation of the cytoskeleton could be a potent regulator of tPA synthesis. However, although a link between cytoskeleton reorganization and upregulation of tPA by HRI is suspected, further studies are necessary to assess it definitely.
In conclusion, in the present study, we demonstrated a link between an enhancement of the endothelial fibrinolytic system and the inhibition of the mevalonate pathway by the well-known hypocholesterolemic agents lovastatin, simvastatin, and compactin. The action of the HRIs involved an inhibition of geranylgeranylated proteins, probably the Rho proteins, and was associated with a disruption of the cytoskeleton. These effects, which were observed also in vivo, suggest that HRIs, through the enhancement of local plasmin generation, might prevent fibrin or extracellular matrix deposition in arterial plaques and acute thrombosis in the injured vessel, which are 2 major determinants of the progression of atherosclerosis48 and cardiovascular mortality.49
| Acknowledgments |
|---|
Received January 7, 1998; accepted June 16, 1998.
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