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Original Studies |
Endocrinology and Metabolism Unit, Surgery Unit (R.D.), University of Louvain, Faculty of Medicine, UCL 5530, B-1200 Brussels; and Pharmaceutical Biology and Phytopharmacology Unit, University of Leuven, Faculty of Pharmaceutical Sciences, KUL (P.J.D.), Van Evenstraat 4, B-3000 Leuven, Belgium
Address all correspondence and requests for reprints to: S. M. Brichard, Unité d’Endocrinologie et Métabolisme, UCL 5530 avenue Hippocrate 55, B-1200 Brussels, Belgium.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Type 1 plasminogen activator inhibitor (PAI-1) is a main regulator of the endogenous fibrinolytic system. It decreases fibrinolysis and promotes the progression of thrombosis (3, 4). Plasma PAI-1 levels are related to overall fatness [body mass index (BMI)] and omental fat in particular and are elevated in obese subjects (3, 5, 6, 7). As PAI-1 is a main risk factor for cardiovascular disease, it may be a pathogenetic link between atherothrombosis and obesity (3, 8). However, the cellular and molecular basis of this connection is still elusive.
Increased fatness itself may contribute to high plasma PAI-1 activity. Indeed, it has recently been discovered that adipocytes have a secretory function (9) and that, besides leptin and other products, these cells can synthesize PAI-1 in rodents and in man (4, 7, 10, 11). Unraveling the mechanisms involved in the regulation of PAI-1 production by adipose tissue is thus essential for our understanding of cardiovascular morbidity associated with obesity. Several endocrine abnormalities are associated with obesity. These include, in particular, hyperinsulinemia, enhanced glucocorticoid turnover (12) and altered sympathetic tone (13, 14). Despite this, the direct role of hormones on PAI-1 production has been studied only in murine adipose cell lines (15) and more recently in human sc fat (16), but never been addressed in human omental fat.
In the present study we therefore investigated the hormonal control of PAI-1 gene expression and production in cultured explants of human adipose tissue. We particularly focused on the effects of glucocorticoids, insulin, and cAMP (as second messenger of catecholamines) in adipose explants from the omental region.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Adipose tissue was obtained from patients undergoing abdominal
surgery after an overnight fast. We first compared two age-matched
subgroups of seven lean (three men and four women; age, 53.7 ±
3.7 yr; BMI, 23.9 ± 1.0 kg/m2) and eight
obese (two men and six women; age, 45.0 ± 4.0 yr; BMI, 40.7
± 1.6 kg/m2) subjects for 24-h PAI-1 production
(obesity being defined as a BMI of 30 kg/m2 or
more). There was no difference in PAI-1 production (micrograms per g
adipose tissue) between the two subgroups (Table 1
). In other experiments, we did not
attempt to discriminate the results in lean from those in obese
subjects, and PAI-1 data from patients with different BMI were pooled.
A total of 59 patients (26 men and 33 women; age, 51.2 ± 2.0 yr;
BMI, 29.7 ± 1.0 kg/m2) were studied. Gender
did not influence the results, in agreement with previous work (11).
Thus, at 24 h, basal PAI-1 messenger ribonucleic acid (mRNA)
levels [optical density (OD)] were 2.8 ± 0.5 in men (n =
10) and 2.9 ± 0.7 in women (n = 18), and PAI-1 secretion
(micrograms per g) averaged 4.4 ± 1.2 in men (n = 8) and
3.8 ± 1.0 in women (n = 13; P > 0.05). All
cases were elective procedures to correct benign conditions
(gastroesophageal reflux, hernia repair, colonic diverticulosis, and
overweight status treated by vertical banded gastroplasty) or malignant
disease (carcinoma of colon). Cancer cases had no evidence of
disseminated disease, and the operation was curative. Localized
colorectal cancer did not modify PAI-1 data in adipose tissue (not
shown). No patients had a history of diabetes, and none had undergone
any significant weight change. Patients receiving endocrine therapy
and/or taking medications known to influence adipose tissue mass or
metabolism were excluded. The study had the approval of the local
ethical committee.
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Adipose tissue or cell culture
One to 60 g omental and sc biopsies were placed in Krebs
buffer, pH 7.4, containing 2% (wt/vol) BSA [Krebs-albumin buffer
(KRAB)] and transported to the laboratory within 5–10 min after
sampling. All visible vessels, coagulation particles, and conjunctive
tissue were removed. Fat tissue was cut with scissors into small pieces
(
4 mm3), then rinsed in phosphate-buffered
saline and incubated in 100-mm petri dishes containing 9 mL MEM with
Earle’s salts supplemented with 10% FCS, 100 IU/mL penicillin, 100
µg/mL streptomycin, and 0.25 µg/mL amphotericin B (Gibco,
Grand Island, NY). In some experiments, FCS was omitted
and replaced by 1% BSA. Approximately 600-1000 mg adipose tissue were
cultured per dish; all conditions were carried out in duplicate, then
material was pooled. The dishes were cultured for up to 48 h at 37
C in an air-CO2 (19:1) atmosphere. The basal
concentration of glucose in fresh medium was 5 mmol/L. The basal
concentrations of cortisol and insulin were extremely low (0.5
nmol/L and 3 pmol/L, respectively). Different hormones or
pharmacological agents were used in various combinations in accordance
with the experimental protocols. When isoproterenol or epinephrine was
tested, ascorbic acid (100 µmol/L) was added to prevent catecholamine
degradation, and in this case MEM medium plus ascorbic acid served as
the control condition. Cell viability, as assessed by low release of
lactate dehydrogenase and triglycerides into the medium under basal
conditions (17), did not change over the course of culture (not shown).
At the end of the experiment, the adipose material was rinsed in
phosphate-buffered saline, collected, immediately frozen in liquid
nitrogen, and stored at -70 C until subsequent RNA extraction.
Aliquots of medium were also saved and stored at -20 C for
measurement of PAI-1 and glucose concentrations.
In some experiments, a sample of adipose tissue was simultaneously processed into isolated adipocytes (and stromal-vascular cells) by collagenase treatment according to the method of Rodbell (18). Briefly, adipose tissue was finely minced and incubated for 1 h in a shaking water bath at 37 C in KRAB with collagenase A (3.3 mg/mL; Boehringer Mannheim, Mannheim, Germany). Digested tissue was filtered through a metallic mesh and centrifuged at 400 x g for 1 min. The floating adipocyte layer was separated from the infranatant medium and washed three times in KRAB. In experiments in which large amounts of tissue were available, the infranatant was also saved and centrifuged again at 400 x g for 3 min, then the pelleted stromal-vascular fraction was washed once and resuspended in KRAB (1 mL/6 g tissue). In methodological studies, the ob gene, which is specifically expressed in adipocytes (19), was highly expressed in the adipocyte fraction, but was not detectable in the stromal-vascular fraction (not shown). For each experimental condition, the adipocytes were obtained from digestion of 1.2–6 g tissue, and the stromal-vascular fraction was obtained from 6 g tissue. Isolated adipocytes and stromal vascular cells were then cultured as described for tissue explants.
RNA extraction and Northern blot analysis
Total RNA was prepared with an acid guanidinium thiocyanate-phenol-chloroform mixture as previously described (19). The concentration of RNA was determined by absorbance at 260 nm. For Northern blot analysis, 10 µg (3.5–7.5 µg for comparisons among explants, isolated adipocytes, and stromal-vascular cells) total RNA were denatured in a solution containing 2.2 mmol/L formaldehyde and 50% (vol/vol) formamide by heating at 95 C for 2 min. RNA was then size-fractionated by 1% (wt/vol) agarose gel electrophoresis, transferred to a Hybond-N membrane (Amersham Pharmacia Biotech, Aylesbury, UK), and cross-linked by UV irradiation. The integrity and relative amounts of RNA were assessed by methylene blue staining of the blots.
The complementary DNA probes for the human PAI-1 and peroxisome
proliferator-activated receptor-
(PPAR) were prepared as follows.
Products of 604 and 457 bp were, respectively, obtained after RT-PCR on
total RNA from human adipose tissue (PAI-1: sense primer,
5'-TTTGGTGAAGGGTCTGCTGTG-3'; antisense primer,
5'-TGCTGCCGTCTGATTTGTGGAA-3'; PPAR: sense primer, 5'-ACCACTCC
CACTCCTTTGAT-3'; antisense primer, 5'-GCATTATGAGACATCCCCAC-3'). The
identity of the appropriate size products was confirmed by mapping with
restriction endonucleases. Human glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) complementary DNA was also amplified by PCR using
commercially available primers (CLONTECH Laboratories, Inc., Palo Alto, CA). Hybridizations with the different
radiolabeled probes were performed as previously reported (19). The
filters were then exposed to Kodak X-Omat AR films
(Eastman Kodak Co., Rochester, NY) for 3–48 h at -70 C
with intensifying screens. The same filters were hybridized
successively with the different probes. The ODs of the mRNA bands on
the blots and of ribosomal 18S RNA on membrane were quantified by
scanning densitometry (Sharp Scanner JX 325 combined with Image Master
Software, Pharmacia Biotech, Uppsala, Sweden). Levels of
specific mRNAs were expressed relative to those of ribosomal 18S RNA.
Internal standards (pooled RNA from two or three patients) were always
loaded on each gel to allow direct comparisons between different
blots.
PAI-1 antigen production
Levels of PAI-1 antigen in the culture medium were measured using a specific enzyme-linked immunosorbent assay as previously described (20). The secretion rate was always expressed as micrograms of PAI-1 released per g wet tissue over the indicated time period. When lean and obese subjects were compared, the secretion rate was also expressed as micrograms of PAI-1 released per µg tissue DNA over the indicated period.
Analytical procedures
Glucose concentrations were measured in medium, before and after culture, using a glucose oxidase method (glucose analyzer, Beckman Coulter, Inc., Fullerton, CA). The glucose consumption rate by explants was calculated as the difference between the amount of glucose in fresh medium and that remaining after 24 h of culture and was expressed as micromoles per g tissue/24 h. DNA was measured in some fresh adipose tissue samples (50–100 mg) using a spectrofluorometric method (21).
Presentation of the results
Results are the mean ± SE for the indicated numbers of patients (i.e. numbers of independent cultures). As data were not normally distributed, they were first normalized by log transformation before statistical analysis (22). Comparisons between different conditions within a same group of patients were made using two-tailed paired Student’s t test or repeated measures of ANOVA followed by the Dunnett’s test (multiple comparisons vs. control) when appropriate. Comparisons between two different groups of subjects (e.g. lean vs. obese) were carried out using unpaired Student’s t test. Differences were considered statistically significant at P < 0.05.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, A and D), in agreement with results
obtained from sc fat (4, 11). However, the transcripts were detectable
after longer exposure of the blots [24–48 h (not shown)
vs. 4–5 h (Fig. 1D)]. These initial rather low levels of
expression were not due to a reduction of the message during transport
to the laboratory, as similar results were obtained in tissue
freeze-clamped immediately after excision (not shown). As described in
sc adipocytes and endothelial cells (4, 23), PAI-1 mRNA and secretion
increased spontaneously in omental fat during the first 12 h of
culture in MEM (Fig. 1, A and B). This rise occurred whether FCS was
present (Fig. 1) or not (data not shown), ruling out the stimulatory
effect of a serum-borne factor. After 12 h of culture, PAI-1 mRNA
levels plateaued (4.7 ± 1.2 and 4.4 ± 0.8 OD at 12 and
24 h, respectively; n = 5) while peptide production was still
increasing (Fig. 1B).
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, inset) further enhanced PAI-1 secretion by adipose
tissue in a time-dependent manner (P < 0.05
vs. respective values without dexamethasone from 8 h
onward; Fig. 1B). The stimulation by the glucocorticoid was preceded by
a 2-fold rise (P < 0.05) in PAI-1 mRNA levels between
4–8 h of culture, an effect that was specific, as GAPDH and PPAR
mRNAs were unaffected by the hormone (Fig. 1, A, C, and D).
The concentration dependence of the effects of dexamethasone on PAI-1
gene expression and protein production was examined after 6 h (24
h; Fig. 2, inset) of culture. The glucocorticoid was
effective at concentrations above 1–10 nmol/L. The maximal effect was
obtained at 100–1000 nmol/L, and it may roughly be estimated that 50%
of this effect occurred at approximately 10–30 nmol/L (Fig. 2).
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). The basal, spontaneous secretion rate
of PAI-1 by omental fat exceeded that by sc fat. The stimulation by
dexamethasone occurred in both adipose sites, although the stimulated
secretion rate remained higher in omental fat. The net absolute effect
produced by 24-h dexamethasone (after subtraction of basal levels)
tended also to be larger (P = 0.057) in omental
(maximal change in PAI-1, 2.2 ± 0.5 µg/g·24 h) than in sc
(1.1 ± 0.3 µg/g·24 h) fat (Fig. 3).
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). Because of the lower concentration
of DNA in obese fat [195 ± 22 ng/g tissue (obese; n = 7)
vs. 292 ± 35 (lean; n = 6); P <
0.05], which is probably due to fewer, but larger, fat cells per g
tissue (11), when PAI-1 data were expressed as micrograms per µg
tissue DNA, secretion rates tended to be higher (40–60%) in the obese
(Table 1). However, this difference did not reach statistical
significance, possibly because of the small number of subjects
studied.
Unlike dexamethasone, 100 nmol/L insulin, either alone or combined with
the glucocorticoid for 24 h, did not affect PAI-1 secretion by
human omental fat. PAI-1 mRNA abundance was also unaffected (Fig. 4). However, insulin exerted its
stimulatory effect on glucose metabolism and accelerated glucose
consumption rates by explants by about 40–45%. Qualitatively similar
results were obtained for PAI-1 mRNA (n = 3; not shown) and
secretion (Fig. 4, inset) in sc adipose tissue.
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).
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. After an overnight culture (18 h)
in MEM, PAI-1 mRNA levels were elevated. When adipose tissue was
cultured for another 12 h in control MEM, these high levels
remained fairly stable. In contrast, the addition of 1 mmol/L
(Bu)2cAMP decreased PAI-1 mRNA abundance, an
effect already detectable after 1 h and maximal (90%) after
4 h. PAI-1 secretion was also attenuated by cAMP; this inhibition
was delayed by about 4–8 h compared with that of mRNA levels and
amounted to about 50% at 12 h.
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). Thus, bromo-cAMP (Br-cAMP) added to
the medium for 12 h markedly decreased PAI-1 mRNA levels [65%
inhibition vs. 90% for (Bu)2cAMP; no
significant difference]. IBMX (a phosphodiesterase inhibitor that
indirectly elevates intracellular cAMP levels) produced a 50% fall in
PAI-1 mRNA abundance. Importantly, epinephrine, an
2- and ß-adrenergic agonist, dose
dependently inhibited the accumulation of PAI-1 mRNA after 8 h of
culture. This effect was reproduced by isoproterenol, a pure
ß-adrenergic agonist. The latter was also shown to inhibit PAI-1
secretion. Propanolol (100 µmol/L), a ß-adrenergic receptor
antagonist, prevented the isoproterenol-induced inhibition of PAI-1
mRNA (73 ± 20% of control levels for isoproterenol plus
propanolol vs. 31 ± 9% for isoproterenol alone;
n = 4; P < 0.05). The negative effect of
(Bu)2cAMP was also observed in sc fat (Fig. 7, inset).
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). In
agreement with a previous study (4), basal PAI-1 mRNA levels in
isolated adipocytes were close to those in explants at 0 and 4 h,
whereas PAI-1 mRNA in stromal-vascular cells tended to be higher.
Importantly, the regulation of PAI-1 mRNA was similar in both isolated
adipocytes and explants: stimulation by dexamethasone and inhibition by
cAMP. In isolated stromal-vascular cells, dexamethasone also produced a
similar relative rise in PAI-1 mRNA (1.6-fold above basal levels),
but cAMP was without significant effect. The contrast between the
pronounced inhibition by cAMP in explants and the minimal effect in
stromal-vascular cells, if any, suggests that alterations in PAI-1 gene
expression in total adipose tissue is mainly explained by alterations
in PAI-1 in adipocytes rather than in stromal-vascular cells.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We confirm that basal production of PAI-1 (micrograms per g tissue) is higher in omental than in sc explants of adipose tissue (4). We further demonstrate that this regional difference persists under stimulated (i.e. dexamethasone) conditions. This difference could partly be explained by depot variations in fat cell size and number. Omental fat cells are slightly smaller but greater in number than sc fat cells (25). Thus, the regional difference in PAI-1 production could be slightly attenuated if secretion was expressed per fat cell. Regional variations in the cellular composition of the stromal-vascular fraction could also potentially contribute to this regional difference in secretion. Whatever the exact mechanism, omental adipose tissue produces more PAI-1 per g than the sc adipose depot. A reverse regional pattern of secretion has been previously observed for leptin, another adipocyte-derived secretory product (25). Taken together, these data extend the concept that adipose tissue is not only a heterogeneous metabolic, but also a secretory, organ.
We next compared basal and stimulated PAI-1 secretion rates by omental adipose explants between lean and obese subjects. We found no differences between the two groups when data were expressed per g tissue. This contradicts a previous report on adipose explants from obese individuals, which were incubated for 2 h and exhibited increased basal PAI-1 production per g tissue (11). This difference may be due to the fact that Eriksson (11) examined adipose tissue from the sc tissue, not from the omental region. Another possibility may be the persisting influence of in vivo circulating factors. After 2 h of culture in basal medium (11), adipose tissue may still be under the influence of circulating stimulatory factors, and an enhanced secretion rate may still ensue, whereas after 24 h of culture, as in our study, this influence may have vanished. Yet, PAI-1 secretion rates tended to be higher in obese than in lean subjects when our data were expressed per µg DNA. This may be explained by the fact that there are fewer fat cells per g tissue in the obese. This suggests that PAI-1 production per fat cell may actually be increased in the obese, a finding possibly due to the larger size of their adipocytes. This is consonant with the positive correlation previously described between adipose tissue secretion of PAI-1 and fat cell volume (11). Thus, the greater contribution of adipose tissue to plasma PAI-1 levels in obesity may be explained by enlarged fat cell volume and increased total fat mass, combined with potential circulating stimulatory factors.
Glucocorticoids may be one of these factors. Dexamethasone stimulates PAI-1 secretion in a dose- and time-dependent manner. This stimulation was preceded by a rise in PAI-1 mRNA and thus involved, at least during earlier time points, pretranslational events. These could be mediated through the binding of the steroid-receptor complex to the glucocorticoid response element that has been identified in the regulatory region of the human PAI-1 gene (26, 27). At later time points (i.e. at 24 h when PAI-1 mRNA no longer increased while PAI-1 protein was still produced), posttranslational mechanisms were also likely to contribute. The stimulation by dexamethasone was observed in both adipocytes and stromal-vascular cells. This finding is consonant with the positive effect of glucocorticoids previously reported in some, but not all (3 of 12), human cell lines, including ones derived from fibroblasts (28). However, the relative contribution of total RNA extracted from stromal-vascular cells and adipocytes to total RNA from adipose explants is currently unknown. In a single report (29), the contribution of the stromal-vascular fraction has been estimated to be 30% of the total RNA from whole human adipose tissue. This value may actually be overestimated in our explants, as all visible vessels and conjunctive tissue were carefully removed from adipose pieces. The marked inhibition of PAI-1 mRNA produced by cAMP in explants despite the lack of an obvious effect in stromal-vascular cells may also support the contention that total RNA from explants contained only a small amount of total RNA from the stromal-vascular fraction. Importantly, the half-maximal concentration for dexamethasone stimulation was about 10–30 nmol/L in explants. These concentrations may be considered to be within the physiological range (from basal levels measured in the morning up to those reached after stressful stimuli) if dexamethasone concentrations are converted into cortisol concentrations on the basis of their respective glucocorticoid potencies of 30:1. The stimulation by dexamethasone was observed in both omental and sc adipose tissues; the effect in the latter is in agreement with a previous report (16). However, the net increment (in absolute values) of PAI-1 induced by dexamethasone was higher in omental fat, probably because of the greater number of glucocorticoid receptors in this adipose region (30). As omental, but not sc, adipose tissue may generate active cortisol (31), constant exposure and increased responsiveness of omental fat to glucocorticoids may contribute to enhanced PAI-1 production in central obesity and, therefore, lead to a greater incidence of cardiovascular disease.
Unlike dexamethasone, insulin, either alone or in combination with the glucocorticoid, had no significant stimulatory effect on PAI-1 secretion by human omental and sc fat. However, insulin has recently been reported to increase PAI-1 production by human sc adipose explants (16). Yet, this increase was moderate (50%; compare with the 2-fold rise that we observed in the presence of dexamethasone) and was not reproduced by isolated human adipocytes. Together, these data may suggest that insulin has no or only a moderate effect on PAI-1 production by human adipose tissue. This is consonant with the lack of effect of euglycemic-hyperinsulinemic clamps on circulating PAI-1 activity in humans (5, 6, 32). However, this contrasts with the marked increase in PAI-1 activity in plasma and PAI-1 mRNA in adipose tissue from mice acutely injected with insulin (15). Insulin also potently increased PAI-1 synthesis by murine 3T3-L1 or -F442 adipocytes (15, 16). Taken together, these data may emphasize species differences in PAI-1 regulation.
cAMP and catecholamines inhibit PAI-1 mRNA and production in human fat. This finding is in agreement with the negative effect of forskolin on PAI-1 secretion in adipose tissue explants (16). The inhibition by cAMP was observed specifically in adipocytes and not in stromal-vascular cells. The latter observation may contrast with previous reports on human endothelial and fibrosarcoma cells (33, 34). However, the cellular composition of the stromal-vascular fraction is heterogeneous, and the ratio of stromal cells to vascular endothelial cells in the pelleted fraction from human abdominal adipose tissue has been only poorly studied. Yet, this fraction has been characterized by immunocytochemistry in breast adipose tissue and found to be composed of approximately 85% stromal (containing preadipocytes), 6% endothelia, about 10% macrophages, and 1% duct epithelia (35). The inhibition of PAI-1 by catecholamines in adipose tissue is novel and may be physiologically relevant. This effect of catecholamines is probably mediated through activation of ß-adrenergic receptors. Indeed, isoproterenol inhibits PAI-1 mRNA more potently than epinephrine on a molar basis, and this effect is prevented by propanolol. This inhibition by catecholamines might be difficult to reconcile with elevated plasma PAI-1 activity in central obesity, as catecholamine action is increased in vitro in the omental depot (36, 37). However, in vivo studies consistently reported blunted lipolytic responses to epinephrine infusion in obese subjects (38, 39, 40, 41), more particularly those with central fat distribution (39). The overall lipolytic rate in vivo reflects mainly the effect of catecholamines on the sc fat depot, which, due to its high proportion of the total fat mass, dominates the response quantitatively. These observations are consonant with the impaired lipolytic action of catecholamines on sc fat cells isolated from subjects with central obesity, a defect partly due to a reduction in sensitivity and/or number of ß2-adrenoceptors (14, 42, 43). As far as adipose tissue responses to catecholamines (estimated by the lipolytic rates) can be extrapolated to PAI-1 production, one would expect an overall impaired action of these hormones (i.e. diminished inhibition) on fat from subjects with central obesity. This would contribute to the associated increase in plasma PAI-1 levels.
Besides hormones, cytokines, in particular tumor necrosis factor-
(TNF), may be involved in PAI-1 regulation. mRNA levels and
secretion of TNF are enhanced in adipocytes from obese rodents and
humans (44, 45). The cytokine is a potent inducer of PAI-1 gene
expression in mouse fat tissue in vivo as well as in 3T3-L1
cells (8, 46). However, the effects of TNF on PAI-1 production by
human adipose explants are still controversial (4, 47).
In conclusion, we provide evidence for a reciprocal regulation of PAI-1 by dexamethasone (positive effector) and cAMP/catecholamines (negative effectors) in cultured human adipose tissue. This regulation operates mainly at the pretranslational level. The stimulation by glucocorticoids (and possibly the impaired inhibition by catecholamines) could contribute to the enhanced production of PAI-1 levels associated with central obesity and thereby be a link between this disorder and cardiovascular disease.
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Acknowledgments |
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Footnotes |
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2 Maître de Recherches and C.M.H. Collaborateur Scientifique
from the Fonds National de la Recherche Scientifique.
Received March 10, 1999.
Revised May 26, 1999.
Revised July 28, 1999.
Accepted August 9, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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is a key
component in the obesity-linked elevation of plasminogen activator
inhibitor 1. Proc Natl Acad Sci USA. 96:6902–6907.? Atherosclerosis. 143: 81–90.
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) or with (
) 50 nmol/L dexamethasone (Dexa) for up to 12 h
are shown. Inset, Evolution of PAI-1 secretion for up to
24 h. GAPDH and PPAR
