© 1999 American Heart Association, Inc.
Thrombosis |
Effects of Fibrate Compounds on Expression of Plasminogen Activator Inhibitor-1 by Cultured Endothelial Cells
From the Atherosclerosis Research Unit, King Gustaf V Research Institute, Department of Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
Correspondence to Lennart Nilsson, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail lennart{at}instmed.ks.se
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Abstract |
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Abstract—The consistent positive correlation between triglyceride and plasminogen activator inhibitor-1 (PAI-1) levels in plasma and the fact that very low density lipoprotein (VLDL) induces secretion of PAI-1 from cultured human umbilical vein endothelial cells (HUVECs) and human hepatoblastoma cells have raised the question of whether fibrate treatment, the main effect of which is a profound lowering of plasma concentrations of VLDL, might improve fibrinolytic function by reducing the plasma levels of PAI-1. However, the findings of controlled clinical trials using various fibrate compounds have been discrepant. ECs express PAI-1 under normal conditions in humans. We therefore examined the effects of several fibrate compounds on PAI-1 expression and secretion by cultured HUVECs and the HUVEC-derived cell line EA.hy926. All fibrate compounds examined had significant effects on PAI-1 gene transcription in the EA.hy926 cells. Low concentrations of clofibric acid and bezafibrate increased PAI-1 transcription and secretion, whereas Wy-14643 increased PAI-1 synthesis in a dose-dependent way. In contrast, both fenofibric acid and gemfibrozil markedly decreased PAI-1 transcription and secretion from HUVECs and EA.hy926 cells. Thus, stimulation of the transcriptional activity of the PAI-1 gene by some fibrates is linked to increased secretion of PAI-1 protein by the cells, whereas the opposite effects occur with other fibrate compounds. Whether the different effects on PAI-1 transcription and secretion by ECs in vitro also reflect differences in treatment effects on the regulation of plasma PAI-1 activity in vivo will have to be determined in larger-scale, controlled clinical trials.
Key Words: PAI-1 • fibrates • endothelial cells • transcriptional activity
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Introduction |
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Fibrate compounds are widely used in the treatment of some forms of diet-resistant hyperlipidemia. The main effect consists of a profound lowering of the plasma concentrations of VLDL lipids and a moderate rise in HDL cholesterol.1 In addition, fibrates have favorable effects on blood coagulation and global fibrinolytic function, which may be at least partly mediated by the lowering of plasma concentrations of triglyceride-rich lipoproteins.1 The consistent positive correlation between triglyceride and plasminogen activator inhibitor-1 (PAI-1) levels in plasma2 and the fact that VLDL induces secretion of PAI-1 from cultured human umbilical vein endothelial cells (HUVECs)3 4 5 and human hepatoblastoma (HepG2) cells4 6 have raised the question of whether fibrate treatment might improve fibrinolytic function by reducing the plasma levels of PAI-1, the fast-acting inhibitor of plasminogen activators and the principal regulator of the endogenous fibrinolytic enzyme system. This issue has now been addressed in a number of short-term, controlled clinical trials using various fibrate compounds. However, the results with respect to lowering of plasma PAI-1 activity have been discrepant: an overall significant effect,7 an effect detectable on subgroup analysis only,8 9 or no effect.10 11 In comparison, studies of the effect of fibrates on PAI-1 synthesis in liver cells in culture have been more conclusive. Gemfibrozil suppresses PAI-1 synthesis in HepG2 cells,12 and a range of fibrate compounds have been demonstrated to suppress PAI-1 synthesis in cultured cynomolgus monkey hepatocytes.13 In addition, gemfibrozil attenuates the augmentation of synthesis and secretion of PAI-1 by HepG2 cells that have been exposed to insulin and its precursors14 and inhibits PAI-1 expression in ECs.15 The fibrate effect in vitro is independent of triglycerides.12 13 It is also notable from the results of the clinical trials that some fibrates producing a comparable triglyceride lowering have widely different effects on plasma PAI-1 activity. Furthermore, a consistent fibrate effect on PAI-1 synthesis in liver cells in vitro, as has been seen with gemfibrozil,12 13 is not accompanied by a consistent lowering of plasma PAI-1 activity in vivo in humans.7 8 9 10 11
The observations made so far in vitro and in clinical trials with fibrates may be interpreted in different ways. Liver cells may not be a significant source of PAI-1 in vivo in humans. This could explain the inconsistency between cell biological and clinical studies with gemfibrozil. In fact, studies using in situ hybridization and immunohistochemistry have indicated that liver cells are not a major source of PAI-1 in healthy individuals,16 whereas ECs16 and adipose tissue17 18 express PAI-1 under normal conditions in humans. The relative contribution of different cells and tissues to the PAI-1 contained in plasma may also differ between individuals, depending on the presence of obesity, hyperlipidemia, inflammation, and the degree of insulin resistance. This, in turn, could account for the heterogeneous PAI-1 responses in clinical trials.7 8 9 10 11 Against this background, we examined the effects of several fibrate compounds on PAI-1 expression and secretion by cultured ECs.
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Methods |
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Materials
Wy-14643 and BRL-49653 were kind gifts from Dr Björn Dahllöf (Astra-Hässle, Mölndal, Sweden), bezafibrate from Dr F. Hammerstein (Boehringer Mannheim GmbH, Mannheim, Germany), fenofibric acid from Dr Alain Munoz (Laboratoires Fournier, Daix, France), and gemfibrozil from Dr Carol Germain (Parke-Davis, Ann Arbor, Mich). Clofibric acid was purchased from Sigma Chemical Co. All fibrates and BRL-49653 were dissolved in dimethyl sulfoxide (DMSO).
Cell Culture
HUVECs were isolated from umbilical cords obtained at normal
deliveries with permission from the local ethics committee. The
umbilical vein was then cannulated and perfused with 50 mL PBS to
remove any blood, after which the vein was filled with 20 mL of 0.1%
collagenase dissolved in PBS and incubated for 15 minutes
at 37°C. The collagenase solution was drained from the
cord and collected, and the cord was gently flushed with 20 mL PBS,
which was added to the collagenase solution. The cells in
these pooled solutions were recovered by centrifugation
at 200g for 5 minutes and seeded out on 9-cm culture dishes
in M199 medium with 20% FCS, antibiotics/antimycotics (Sigma A-9909),
and 25 µg/mL EC growth supplement (Sigma E-2759). The cells were
subcultured when confluent onto 0.2% gelatin (in PBS) -coated dishes.
Cells from pooled, multiple cords were used for experiments until the
fourth passage. The endothelium-derived cell line
EA.hy926 (a kind gift from Dr C.-J.S. Edgell, University of North
Carolina, Chapel Hill) was cultured in Dulbecco's modified Eagle's
medium (DMEM) with high glucose, supplemented with 10% FCS, 100
mmol/L hypoxanthine, 0.4 mmol/L aminopterin, 16 mmol/L
thymidine, penicillin, and streptomycin as
described.19
Determination of PAI-1 Protein Production
Semiconfluent cultures of HUVECs or EA.hy926 cells were
incubated for 8 to 10 hours in M199 or DMEM medium, respectively,
containing either 1% charcoal-treated FCS or 2% untreated FCS. This
incubation was followed by a 14-hour incubation with fibrates added in
the same type of medium. After the conditioned medium was collected and
centrifuged at 10 000 rpm for 5 minutes, the PAI-1 protein
concentration in the medium was quantified using an ELISA (TintELIZE
PAI-1, Biopool), which detects active and inactive (latent) forms of
PAI-1, as well as tissue plasminogen
activator/PAI-1 complexes. The cells were trypsinized and
counted. PAI-1 production was expressed as a percentage of
control (vehicle containing the same amount of DMSO).
MTT Assay
Cell viability was assessed by the MTT assay (Sigma) according
to the manufacturer's instructions. This assay is based on the
cellular reduction of MTT by mitochondrial dehydrogenase of viable
cells to a blue formazan product, which is measured
spectrophotometrically at 570 nm.
Northern Blot Analysis
Semiconfluent cultures of EA.hy926 cells were incubated for 8 to
10 hours in DMEM containing 2% FCS, followed by an 8-hour incubation
with fibrates added to the same type of medium. Total RNA from the
EA.hy926 cells was isolated according to the RNeasy handbook (Qiagen).
Northern blotting and hybridization on DuPont GeneScreen Plus nylon
membranes (NEN Research Products) were performed according to the
manufacturer's protocol. Blots were hybridized with
106 counts per minute per milliliter of
[
-32P]dCTP-labeled SfiI and
BglII fragment (1255 bp) of the cDNA for PAI-1 (courtesy of
Dr Tor Ny, Department of Biochemistry and Biophysics, University of
Umeå, Umeå, Sweden).
Transfection Assay
EA.hy926 cells were transfected using a calcium phosphate
precipitation method as described by Sambrook et al.20
pRSV–ß-galactosidase-control vector (Promega) was cotransfected as
an internal control. The construction of the PAI-1 chloramphenicol
acetyltransferase (CAT) plasmids has been described
elsewhere.21 The 4G-PAI-pCAT construct comprises human
PAI-1 sequences -804 to +17. The cells were transfected at 80% to
90% confluence. One to 3 hours before transfection, the dishes
received fresh complete medium. Cells were incubated for 4 hours with
calcium phosphate–precipitated DNAs (15 µg plasmid per 90-mm dish).
After a 2-minute 15% (vol/vol) glycerol shock, fresh medium containing
2% FCS and fibrates was added, and the cells were harvested for
transient expression 16 to 18 hours later. CAT activity was
analyzed according to Sambrook et al.20
Statistical Methods
For each drug, differences in the effects of various
concentrations of fibrate compounds on PAI-1 protein production
and PAI-1 promoter activity were tested by ANOVA, with the Scheffe test
used as a post hoc test.
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Results |
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Effects of Fibrates on PAI-1 Production and mRNA Levels in ECs
Fibrates were incubated with HUVECs or with the HUVEC-derived cell line EA.hy926, and PAI-1 that accumulated in the culture medium was measured using an ELISA. Because the nuclear hormone receptor, peroxisome proliferator-activated receptor-
(PPAR), is
activated by fibrates,22 we also studied the
effects of the thiazolidinedione compound BRL-49653. Thiazolidinediones
activate PPAR
,23 and BRL-49653 was used to
further substantiate the notion that any suppression of PAI-1
production obtained with fibrates in ECs could be linked to
PPAR activation. Influences on PAI-1 accumulation are summarized in
Table 1
. Because identical results were
obtained when cells were incubated with medium containing either 1%
charcoal-treated or 2% untreated FCS, experiments were pooled.
Clofibric acid, bezafibrate, and Wy-14643 increased the PAI-1
production from both cell types. The increase in PAI-1
production with clofibric acid and bezafibrate occurred at
fairly low concentrations and disappeared at higher concentrations of
the compounds. Wy-14643, on the other hand, produced a graded increase
in PAI-1 production from the ECs with increasing concentrations
of the compound. In contrast, fenofibric acid, gemfibrozil, and
BRL-49653 all produced a marked decrease in PAI-1 production.
The MTT assay showed that cell viability was unaffected by the fibrate
and BRL-49653 concentrations used in these experiments. However, higher
fibrate concentrations (200 µmol/L of clofibric acid and
gemfibrozil and 400 µmol/L of bezafibrate, fenofibric acid, and
Wy-14643) markedly decreased cell viability. The basal
production of PAI-1 as seen in the control (DMSO added) was 100
to 120 ng/105 cells and 20 to 30
ng/105 cells in HUVECs and EA.hy926 cells,
respectively.
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Because each fibrate influenced the production of PAI-1
from HUVECs and EA.hy926 cells in a similar fashion, Northern blot and
transfection experiments (shown below) that require many cells were
performed in EA.hy926 cells only. Northern blot analysis of
mRNA levels was in agreement with the finding that some fibrates
increase the production of PAI-1 by EA.hy926 cells, whereas
other fibrates decrease PAI-1 production from these cells.
Panel A of the Figure shows a
representative Northern blot analysis of the
mRNA recovered from EA.hy926 cells when incubated for 8 hours with
200 µmol/L of fenofibric acid or Wy-14643. Quantification of the
Northern blot experiment is shown in panel B of the Figure. Fenofibric
acid significantly decreased the levels of both the 3.2- and the 2.2-kb
PAI-1 transcripts, whereas Wy-14643 increased the levels of the 2 PAI-1
transcripts.
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Effects of Fibrates on PAI-1 Transcription
A transfection assay was performed using a 804-bp fragment of the
PAI-1 promoter coupled to the CAT gene. As summarized in Table 2, clofibric acid, bezafibrate, and
Wy-14643 significantly increased PAI-1 transcription in EA.hy926 cells.
For clofibric acid and bezafibrate, this effect occurred at a fairly
low concentration of the compound and disappeared at higher
concentrations. The opposite effect was obtained with fenofibric acid,
gemfibrozil, and BRL-49653 (Table 2).
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Discussion |
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This study shows that individual fibrate compounds have different effects on PAI-1 secretion by cultured ECs and that these differences are accounted for by different effects on PAI-1 transcription.
The diverse effects of fibrate compounds on EC expression of PAI-1
observed in the present study contrast with the uniform,
dose-dependent suppressive effect of fibrates on PAI-1 synthesis seen
in cultured cynomolgus monkey hepatocytes.13
The molecular mechanisms underlying these differences remain unknown.
The regulatory mechanism by which the fibrate effect on PAI-1
expression is exerted in the cynomolgus monkey hepatocyte
is indicated to involve activation of PPAR/retinoid X
receptor-.13 PPAR expression in HUVECs and EA.hy926
cells is unknown. However, the diverse effects of fibrates indicate
that PAI-1 regulation in ECs by fibrate compounds is not solely
mediated by PPAR. Furthermore, the lowering effect of the
thiazolidinedione BRL-49653 on PAI-1 transcription and secretion by
HUVECs and EA.hy926 cells suggests that PPAR is implicated
in regulating PAI-1 expression in ECs. Some differences in experimental
procedures also need to be considered. Higher fibrate concentrations,
longer incubation times, and 10% bovine serum–supplemented medium
(vol/vol) were used in the cynomolgus monkey hepatocyte
studies by Arts et al.13 In contrast, we used cells that
were incubated with medium containing 1% charcoal-treated FCS or 2%
untreated FCS as well as lower fibrate concentrations to avoid the
confounding effects of a range of serum substances known to induce
PAI-1 and to optimize the conditions for demonstrating differential
effects of individual fibrate compounds. It is notable in this context
that opposite effects of gemfibrozil and bezafibrate on PAI-1 secretion
have been demonstrated in HepG2 cells incubated in serum-free
medium.24
The concept that fibric acid derivatives could improve fibrinolytic function by lowering plasma PAI-1 activity originates from the fact that fibrates markedly lower the concentrations of VLDL1 and from the observation that a strong, positive correlation exists between triglyceride and PAI-1 levels in plasma.2 Furthermore, VLDL induces PAI-1 secretion from cultured HUVECs3 4 5 and human hepatoblastoma (HepG2) cells.4 6 However, clinical trials have demonstrated that fibrates producing a comparable triglyceride lowering have widely different effects on plasma PAI-1 activity.7 8 9 10 11 This finding in vivo along with previous cell biological studies12 13 and the present in vitro data from ECs strongly indicate that any fibrate effects on plasma PAI-1 activity in humans are at least partly a result of direct effects of the drug on PAI-1 synthesis in liver cells and/or ECs. The question then arises as to whether the diverse fibrate effects on PAI-1 expression in ECs observed in the present study could explain some of the discrepancies between the previous clinical trials. Clearly, inferences from cell culture studies to the situation in vivo should, for several reasons, be made with caution. PAI-1 synthesis occurs in a number of different cell types in culture, including ECs, hepatocytes, smooth muscle cells, and adipocytes, and is regulated by a large number of substances (reviewed in Reference 2525 ). However, the behavior of cultured cells may not be identical to that of the same cell type in vivo. Furthermore, metabolic perturbations and the relative importance of different regulatory mechanisms may differ between participants in various clinical trials. These restrictions notwithstanding, some reflections can be made. Gemfibrozil has been indicated to reduce plasma PAI-1 activity in patients with primary hypertriglyceridemia7 26 27 and in survivors of myocardial infarction.8 This compound also markedly decreased PAI-1 transcription and secretion from HUVECs and EA.hy926 cells in the present study and has previously been shown to suppresses PAI-1 synthesis in HepG2 cells12 and cultured cynomolgus monkey hepatocytes.13 Bezafibrate, on the other hand, seems not to lower PAI-19 28 and even tended to increase plasma PAI-1 activity in the BECAIT study (A.H. et al, unpublished data, 1999). In vitro in ECs, bezafibrate increased PAI-1 transcription and secretion at lower concentrations but had no effect at higher concentrations.
In summary, individual fibrate compounds have diverse effects on PAI-1 expression in ECs, the molecular mechanisms of which remain unknown. Whether the different effects on PAI-1 transcription and secretion by ECs in vitro also reflect differences in treatment effects on the regulation of plasma PAI-1 activity and global fibrinolytic function in vivo in humans will have to be determined in larger-scale, controlled clinical trials comparing different fibrates.
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Acknowledgments |
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This project was supported by grants from the Swedish Medical Research Council (8691 and 11807 to A.H.), the Swedish Heart-Lung Foundation (to A.H.), the European Commission (HIFMECH study, contract BMH4-CT96-0272 to A.H.), the Marianne and Marcus Wallenberg Foundation (to A.H.), the Petrus and Augusta Hedlund Foundation (to A.H.), the King Gustaf V 80th Birthday Foundation (to A.H.), the Foundation for Old Servants (to A.H. and P.E.), and the Professor Nanna Svartz Foundation (to A.H. and P.E.). We are grateful to Barbro Burt for excellent technical assistance.
Received September 25, 1998; accepted November 17, 1998.
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