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From the Department of Medicine, The University of Vermont College of
Medicine, Burlington (B.E.S., J.W.-M., D.J.S., K.M.); and Massachusetts
General Hospital, Boston (R.E.H., H.G.).
Correspondence to Dr Burton E. Sobel, Department of Medicine, FAHC-MCHV Campus, Fletcher 311, 111 Colchester Ave, Burlington, VT 05401. E-mail burton.sobel{at}vtmednet.org
Methods and Results—Samples acquired by directional
coronary atherectomy from 25 patients with type 2 diabetes and
18 patients without diabetes were characterized qualitatively
histologically for cellularity and by
immunohistochemistry visually and qualitatively and by quantitative
image analysis for assessment of urokinase-type
plasminogen activator (u-PA) and PAI-1.
Patients with and without diabetes were similar with respect to
demographic features and the distribution and severity of
coronary artery disease. Substantially more PAI-1 and
substantially less u-PA were present in the atherectomy samples
from subjects with diabetes.
Conclusions—The disproportionate elevation of PAI-1 compared with
u-PA observed in atheromatous material extracted from
vessels of diabetic subjects is consistent with increased gene
expression of PAI-1 in vessels as well as the known increase of PAI-1
in blood, presumably reflecting increased synthesis. The increased
PAI-1 detected in the atheroma may contribute in vivo to
accelerated or persistent thrombosis underlying acute occlusion and to
vasculopathy exacerbated by clot-associated mitogens in the vessel
wall. Because the changes were observed to be associated with insulin
resistance and type 2 diabetes mellitus, they may be modifiable by
reduction of insulin resistance with insulin sensitizers and stringent
control of hyperglycemia.
We and others6 7 8 have observed
consistent elevations of concentrations in blood of PAI-1
reflected by reduced fibrinolysis in response to venous
occlusion, a phenomenon consistent with intermittent
persistence of microthrombi in vessels with consequent adverse effects
of clot-associated mitogens on the vessel wall accelerating
macrovascular disease.
Subjects with type 2 diabetes who undergo percutaneous
transluminal coronary angioplasty exhibit 4-fold higher 5-year
mortality than do nondiabetic subjects treated comparably and with
similar lesions.9 10 The increase appears to be
attributable largely to restenosis. As judged from
analysis of human and porcine vessels, early atherosclerotic
lesions and complex plaques are characterized by disproportionate
increases in PAI-1 within the vessel wall compared with concentrations
of u-PA and t-PA.11 Furthermore, rats genetically
predisposed to insulin resistance, postprandial hyperglycemia, and
macroangiopathy late in life exhibit changes in the walls of vessels
analogous to those seen in type 2 diabetic human
subjects.12 Explants of vascular smooth muscle
cells from vessels of the animals predisposed to
atherosclerosis exhibit higher rates of proliferation
in vitro than do cells from controls, even when the explants have been
obtained many months before the time of appearance, in vivo, of
macroangiopathy.13
These observations led us to hypothesize that one of the factors
contributing to macroangiopathy in type 2 diabetes and to the
accelerated restenosis compromising the long-term efficacy of
angioplasty in diabetic subjects is a disproportionate elevation of
PAI-1 in vascular wall components and atheroma. Such an
elevation would be likely to predispose to thrombosis and its
persistence, thereby increasing the risk of acute coronary
events and possibly restenosis potentiated by clot-associated
mitogens.
Coronary atherectomy samples were excised selectively and
retrieved from coronary atherosclerotic lesions by
conventionally performed DCA.
Medications
DCA was successful in each case. There was no associated mortality. The
extent of residual stenosis was reduced to <50% of the
initial stenosis universally.
Characterization of Atherectomy Specimens
Qualitative Assessments
Quantitative Assessments
Preparation of Specimens for Analysis
Immunoperoxidase Staining
The primary antibodies used were monoclonal antihuman PAI-1
(product No. 3785) (10 µg/mL); monoclonal antihuman u-PA
(product No. 3689) (10 µg/mL) (both acquired from American
Diagnostica); monoclonal anti–smooth muscle
After incubation at 37°C, sections were washed three times in PBS and
treated with secondary antibody (DAKO Envision System, a horseradish
peroxidase polymer system conjugated with secondary antibodies) that
reacted with mouse primary antibodies (DAKO). Again, the sections were
incubated at 37°C for 30 minutes, washed three times in 0.05 mol/L
Tris-hydroxyaminomethane (Tris), pH 7.6, and treated with a substrate
solution consisting of 25 mg DAB (Sigma Chemical Co) and 17.5 µL 30%
H2O2 in 50 mL Tris for 5
minutes at room temperature followed by three washes in PBS.
For conventional histology, counterstaining was performed with Mayer's
hematoxylin solution (Sigma Chemical Co) for 3 minutes. The sections
were then washed three times in PBS and dehydrated through 50%, 75%,
95%, and 100% ethanol. They were washed twice in xylene before being
mounted under coverslips with Permount.
Grading of Immunohistochemical Staining Intensity and
Cellularity
Statistical Analysis
Cellularity scores assessed visually and hence qualitatively did not
differ significantly for tissues from the two groups of patients (Table 1
Concentrations of PAI-1 in blood are elevated in association with
diverse states of insulin resistance. A salient example is the
genetically obese mouse (ob/ob) as reported initially by Samad and
Loskutoff.14 The same laboratory demonstrated
high concentrations of PAI-1 in murine adipose tissue in vivo and its
augmentation in response to tumor necrosis
factor-
The present results underscore the potential pathogenetic
importance of derangements in expression of fibrinolytic system
proteins in tissues as well as in blood. Insulin augments expression of
PAI-1 in HepG2 cells (a human hepatoma cell line). Both insulin and its
precursor, proinsulin, in concentrations consistent with those
prevailing in blood in subjects with type 2 diabetes mellitus, augment
elaboration of PAI-1 from these cells.8
Furthermore, insulin augments PAI-1 elaboration by
endothelial cells in the presence of cocultured
vascular smooth muscle cells, again in concentrations
consistent with those seen in blood in subjects with type 2
diabetes.21 Administration of either insulin or
proinsulin to experimental animals maintained under
euglycemic conditions leads not only to augmented
concentrations of PAI-1 in blood but also to augmented concentrations
of PAI-1 protein and PAI-1 mRNA in vessel
walls.22 Although administration of insulin to
human subjects with type 2 diabetes has not been shown to elevate PAI-1
in blood, possibly because of the concomitant reduction in proinsulin
secretion as noted by Jain et al,23 we have
recently found it to do so in human cells in a setting in which the
metabolic milieu simulates that associated with type 2
diabetes.24 Taken together with the present
observations, these findings suggest that vascular wall PAI-1 synthesis
is a potentially useful target for measures designed to reduce the
acceleration of macroangiopathy typical of type 2 diabetes and to
reduce the risk of thrombotic coronary occlusion underlying
many acute coronary events.
Conclusions
Received December 1, 1997;
revision received January 22, 1998;
accepted January 28, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Increased Plasminogen Activator Inhibitor Type 1 in Coronary Artery Atherectomy Specimens From Type 2 Diabetic Compared With Nondiabetic Patients
A Potential Factor Predisposing to Thrombosis and Its Persistence
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Inhibition of
fibrinolysis attributable to elevated concentrations of
plasminogen activator inhibitor
type 1 (PAI-1) in blood is associated with insulin resistance,
hyperinsulinemia, and type 2 diabetes mellitus.
Because we have shown that insulin can stimulate PAI-1 synthesis in
vivo and because accelerated vascular disease is common in such
patients as well, we hypothesized that increased PAI-1, potentially
predisposing to thrombosis, acute occlusion, and accelerating
atherosclerosis because of thrombus-associated
mitogens, would be present in excess in atheroma from
type 2 diabetic subjects.
Key Words: diabetes mellitus • coronary disease • fibrinolysis • insulin • thrombosis
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
The prevalence of
coronary artery disease in type 2 diabetic subjects is 
4-fold
greater than that in nondiabetic subjects.1 Even
with stringent control, an increased risk for macrovascular disease in
type 2 diabetes persists. Accordingly, the possibility exists that the
combined hyperproinsulinemia and hyperinsulinemia
typical of type 2 diabetes may exert adverse influences on the vessel
wall independent of hyperglycemia and other derangements of
intermediary metabolism typically present in both type
1 (insulinopenic) and type 2 (hyperinsulinemic and
dysinsulinemic) diabetes.2 3 4 5
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients Studied
Twenty-five patients with type 2 diabetes and 18 without
clinical evidence of diabetes were studied between April 1996 and March
1997 at the time of DCA mandated by clinical indications (performed by
H.G. at the Massachusetts General Hospital). The two groups of patients
(diabetic and nondiabetic) were similar with respect to clinical
indications for DCA, use of heparin during all procedures, absence of
gross thrombus detected angiographically, initial success of the
procedure, and other characteristics, including age and sex (Tables 1
and 2)
and the nature (primary or restenotic) and distribution of
culprit coronary arterial lesions (Table 3).
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Table 1. Biochemical Variables in Specific Categories of
Patients
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Table 2. Patient Characteristics
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Table 3. Characteristics of Coronary Disease
Each patient was pretreated with aspirin 325 mg/d and
dipyridamole 50 mg every 6 hours initiated 24 hours
before DCA and continued after hospital discharge. Heparin was
administered as an initial bolus of 10 000 U IV after insertion of an
arterial sheath and as additional 2500-U boluses every 30
minutes as needed to maintain the activated clotting time
between 250 and 300 seconds throughout the DCA procedure.
Atherectomy samples were assayed for u-PA and PAI-1 by
immunohistochemistry (immunoperoxidase
staining).14 In addition, the material was
assayed for cellularity. Analysis was performed as follows.
A visual grading scale (+ to ++++) was used for the assessment
of the intensity of immunohistochemical staining as shown in Figures 1 and 2. An
analogous grading scale (+ to ++++) was used for assessment of
cellularity as shown in Figure 3.
Sections from the DCA-extracted material were characterized by
comparison of the sections with the grading scale sections by two
observers who were blinded to the characteristics of the patients. Each
observer evaluated a minimum of three sections per block (selected
randomly and independently), evaluated three to five fields per section
(again selected randomly and independently), and scored each field on a
0 to 4+ scale for intensity and a 0 to 4+ scale for the extent of
distribution of positive staining to yield an average result for each
atherectomy sample. Results were obtained by averaging the average
values from each observer for each sample.
View larger version (111K):
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Figure 1. Immunohistochemical staining of PAI-1 identifying
scale used to grade samples. Each sample was scored in relation to
reference scale shown here by two observers blinded to status of
patients from whom samples were obtained. In each case in this and
subsequent figures, negative controls were obtained with normal murine
IgG substituted for primary antibody as shown in Figure 4 
.
Magnification x100.
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Figure 2. Immunohistochemical staining of u-PA defining
scale used to grade samples applied in a fashion analogous to that for
PAI-1, as noted in legend to Figure 1 . In each case in this and
subsequent figures, negative controls were obtained with normal murine
IgG substituted for primary antibody as shown in Figure 4.
Magnification x100.
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Figure 3. Grading scale used to score each sample with
respect to cellularity and applied in a fashion analogous to that used
with grading scales noted in legends to Figures 1 and 2. Sections were
stained with hematoxylin, which stains nuclei blue. Arrows point to
regions with cellularity of increasing extent in A through D.
Magnification x100. Note: These samples were also stained for
PAI-1.
Quantitative image analysis of the sections was
performed by observers blinded with respect to the patients from whom
samples were obtained, as follows:15
immunoperoxidase-stained slides were viewed with an Olympus BX-50
upright light microscope. Digital gray-scale images were acquired with
an attached Sony DXC-960MD/LLP charged coupled device camera connected
via an RS-170 cable to a frame grabber board in a Sun SPARCstation 5
computer. Image collection and analysis was performed with
IMIX/IMAGIST Version 8 software (Princeton Gamma Tech). Data
for all images of each type were collected with identical camera
settings, followed by selection of regions of interest on the digitized
image. Gray-scale values (pixel intensities) within the regions of
interest were plotted as histograms, and minimum, maximum, and mean
pixel intensity values were calculated with conventional software.
These values were used to compare intensity of immunoperoxidase
reaction products in vessels from diabetic and nondiabetic
subjects. Data are expressed as intensity units above values with mouse
IgG used as a control for comparison. To verify the
representative nature of computed values used for
comparisons between groups, coefficients of variation were evaluated
for repeated readings of the same field, values from multiple fields
within the same section, and multiple sections within a block from a
given sample (6 to 10 values for each). Results were 0.26%, 2.3%, and
3.6%. The low values of these coefficients of variation are
consistent with the validity of between-group comparisons of
values obtained within each group.
The DCA samples were fixed in ethanol for a minimum of 48 hours
and processed conventionally for histochemical analysis.
Sections 6 µm thick were prepared and stained with antibodies
specific for each protein of interest as described below. Three
sections from each tissue sample were assayed for each component, and
results were averaged to obtain a score for each variable in each
DCA sample.
Immunoperoxidase staining with the antibodies selected was
performed as follows. Tissue sections were deparaffinized through two
incubations in xylene, 5 minutes each, followed by successive
incubations in ethanol (100%, 95%, 75%, and 50%) for 3 minutes each
and subsequently in PBS for 3 minutes. All incubations were performed
at room temperature. Sections were treated with 0.25% trypsin for 15
minutes at ambient temperature, followed by two washes in PBS. They
were then placed in 0.75%
H2O2/75% methanol for 30
minutes, washed twice in PBS, and maintained in a humidified chamber in
3% BSA in PBS for 30 minutes at room temperature. Subsequently, they
were treated with 10% normal goat serum for 30 minutes, followed by
exposure to primary antibody in a humidified chamber at 37°C for 30
minutes. 
-actin
(from Sigma Chemical Co) as a positive control; anti-CD44 (acquired
from R+D Systems); and normal mouse IgG (from Sigma Chemical Co) as a
negative control. The anti–human PAI-1 antibody recognizes both free
PAI-1 and PAI-1 complexed to plasminogen
activators. The anti–human u-PA antibody recognizes free
u-PA and receptor-bound u-PA. It also recognizes u-PA complexed with
PAI-1 as verified in our laboratory and shown in Western blots.
Grading scales are shown in Figures 1 through 3. The absence of
staining for PAI-1 and/or u-PA in negative controls is shown in Figure 4. This figure also demonstrates the
colocalization of PAI-1 with smooth muscle -actin–positive cells,
indicating that the PAI-1 seen was present primarily in smooth
muscle cells. Values in samples were based on the intensity of staining
and the percentage of tissue stained, both referenced to the sections
in the grading scale used to define the 4-point grading scale as judged
independently by two observers evaluating independently and randomly
identified fields (three to five per section) and blinded with respect
to the characteristics of the patients from whom the sections had been
obtained.
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Figure 4. Concordant localization of
immunostained PAI-1 and -actin indicative of vascular
smooth muscle cells. Serial sections stained with PAI-1 antibody (A)
and -actin antibody (B). PAI-1 was detected virtually exclusively in
vascular smooth muscle cells characterized by presence of -actin. C
and D show two negative controls illustrating lack of staining with
normal mouse IgG used instead of primary antibody compared with results
in A and B, respectively. As noted in text, other negative controls
were obtained routinely to verify specificity of
immunostaining with antibody against PAI-1, u-PA, or
-actin.
Comparisons between groups were performed with two-tailed
Student's t tests for unpaired samples. Differences with
values of P
0.05 were considered to be significant.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients with and without diabetes did not differ with
respect to age (Table 1) or other demographic features (Table 2). The
nature (primary or restenotic) and distribution of
coronary lesions were generally similar in the two groups
(Table 3). As shown in a representative example of a
photomicrograph of immunostained material in Figure 5 and in Table 1, atherectomy samples
from subjects with diabetes appeared to exhibit less u-PA than those
from subjects without diabetes (1.28±0.16 [SE] arbitrary units
compared with 2.62±0.26), P<0.01, a difference
consistent with decreased atheroma-associated cell
surface–mediated proteo(fibrino)lytic system capacity. By contrast,
tissue from diabetic subjects appeared to exhibit significantly more
PAI-1 (2.32±0.19) than tissue obtained from nondiabetic subjects
(1.55±0.17, P<0.01), as shown in the example in Figure 6, and by results in Table 1. Results
with automated image analysis were consistent with the
qualitative differences observed visually (Table 1). Thus, as shown in
Table 1 and Figure 7, samples from
patients with diabetes exhibited consistently more PAI-1 and
consistently less u-PA than samples from patients without
diabetes. These differences were consistent in subsets of
patients with primary and restenotic lesions (Table 1) and
evident regardless of the nature of the treatment of diabetes (Table 3).
View larger version (130K):
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Figure 5. Intensity and distribution of
immunohistochemical staining of u-PA in samples from
representative patients without diabetes (A and B)
compared with those in samples from patients with type 2 diabetes (C
and D). Both distribution and intensity of staining were generally less
in samples from subjects with diabetes (Table 1 ). In each case in this
and subsequent figures, negative controls were obtained with normal
murine IgG substituted for primary antibody as shown in Figure 4. Dark
brown in A reflects intense staining with u-PA antibody in area rich in
matrix. Intensities of staining in B and D are similar and are included
in this figure to demonstrate that intensity of staining in a given
section from a diabetic patient may closely resemble intensity of
staining in another given section from a nondiabetic subject. However,
in general, staining with u-PA antibody in sections from
diabetic patients was less intense and less widely distributed than
that in sections from nondiabetic subjects as shown in Table 1 and
confirmed by quantitative image analysis results shown in
Figure 7. Magnification x100.
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Figure 6. Intensity of immunohistochemical staining for
PAI-1 in representative samples from patients without
diabetes (A and B) compared with those from
representative patients with type 2 diabetes (C and D).
Intensity and distribution of staining were generally greater in
samples from subjects with diabetes than those without diabetes (Table 1 ). In each case in this and subsequent figures, negative controls were
obtained with normal murine IgG substituted for primary antibody as
shown in Figure 4. Magnification x100.
View larger version (28K):
[in a new window]
Figure 7. Results of quantitative image
analysis (IA) for detection of u-PA and PAI-1 in nondiabetic vs
diabetic subjects (A), nondiabetic vs all diabetic subjects and only
diabetic subjects treated with insulin, sulfonylureas, or both (B),
diabetic and nondiabetic subjects with primary lesions (C), and
diabetic vs nondiabetic subjects with restenotic lesions (D).
*P<0.05 for comparisons between diabetic and
nondiabetic subjects in each case. ) (1.76±0.20 [SE] arbitrary units compared with 2.02±0.21 in
nondiabetic subjects). These results are not inconsistent with
proliferation of vascular smooth muscle cells within the
arterial wall of the vessels from diabetic subjects in situ
in view of the nature of the coronary atherectomy procedure
used, which extracted material not necessarily
representative of cellularity within the entire vessel
wall but more likely to be indicative of overall cellularity in complex
plaques.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Results in the present study are consistent with the
hypothesis that one of the contributors to the development of
accelerated macroangiopathy in type 2 diabetes mellitus is altered
tissue expression of components of the fibrinolytic system within
atheroma and presumably therefore arterial
walls; specifically, disproportionate elevations of concentrations of
PAI-1 with respect to concentrations of u-PA. The results support the
possibility that inhibition of the fibrinolytic system activity in situ
in syndromes of insulin resistance and
hyperinsulinemia, including type 2 diabetes,
predisposes to thrombosis and its persistence, setting the stage for
thrombotic coronary artery occlusion and accelerated
atherosclerosis or restenosis in response to
clot-associated mitogens. The present results demonstrate an
increase in total PAI-1 (free plus plasminogen
activator–complexed PAI-1) and a decrease in total u-PA
(free and receptor bound) in the specimens from the diabetic patients.
Thus, even if some of the PAI-1 detected is complexed with some of the
u-PA (an interaction possible with the two-chain species), the amount
of free PAI-1 appears to be increased. Accordingly, the results
indicate that immunohistochemically detectable PAI-1 is increased and
immunohistochemically detectable u-PA is decreased in atherectomy
specimens acquired by extraction and conventional fixation from the
diabetic compared with the nondiabetic subjects. Thus, they suggest
that the hyper(pro)insulinemia associated with type 2 diabetes leads to
elevated intramural PAI-1 that can contribute to an increased risk of
thrombosis and accelerated vasculopathy. .15 Consistent with these
observations, elevations of PAI-1 have been seen in human subjects with
obesity, type 2 diabetes mellitus, and the polycystic ovary
syndrome.6 16 17 18 19 20 We recently demonstrated that
weight reduction induced by modest caloric restriction in elderly obese
subjects leads to a decline in prevailing concentrations of PAI-1 in
blood paralleled by augmentation of functional activity of the
fibrinolytic system.20 When we administered
troglitazone, a thiazolidinedione known to enhance insulin sensitivity,
to patients with the polycystic ovary syndrome in whom concentrations
of PAI-1 in blood are markedly elevated, concentrations of PAI-1 in
blood declined markedly.19 If such changes are
paralleled by altered expression of PAI-1 within
atheroma and/or vessel walls, as appears likely judged from
the result in the present study, augmentation of insulin
sensitivity may prove to be effective in ameliorating disproportionate
elevation of vascular wall PAI-1 and its potential pathogenetic impact
on thrombosis and the evolution of macroangiopathy.
The results obtained in this study are consistent with the
hypothesis that a disproportionate elevation of PAI-1 not only in blood
but also in extracted atheroma and presumably vessel walls
is characteristic of and perhaps a direct consequence of
hyperinsulinemia and hyperproinsulinemia typical of
insulin-resistant states, including type 2 diabetes mellitus.
Accordingly, reduction of insulin through diet and exercise programs,
optimal control of hyperglycemia, and perhaps concomitant use of
insulin sensitizers, such as thiazolidinediones, offers particular
promise for attenuating progression of macrovascular disease
exacerbated by thrombosis in insulin-resistant states,
including type 2 diabetes mellitus.
Selected Abbreviations and Acronyms
DCA
=
directional coronary atherectomy
PAI-1
=
plasminogen activator inhibitor
type 1
t-PA
=
tissue plasminogen activator
u-PA
=
urokinase plasminogen activator
Acknowledgments
The assistance of Tomohiro Sakamoto, MD, Douglas J. Taatjes,
PhD, and Satoshi Fujii, MD, of the Department of Medicine, The
University of Vermont College of Medicine, Burlington, is
appreciated.
Footnotes
Presented at the 70th Scientific Sessions of the American Heart Association, Orlando, Fla, November 10–13, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-591).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
and lipopolysaccharide. J
Clin Invest. 1996;97:37–46.[Medline]
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B. E. Sobel, D. J. Taatjes, and D. J. Schneider Intramural Plasminogen Activator Inhibitor Type-1 and Coronary Atherosclerosis Arterioscler. Thromb. Vasc. Biol., November 1, 2003; 23(11): 1979 - 1989. [Abstract] [Full Text] [PDF]
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S. S. Anand, Q. Yi, H. Gerstein, E. Lonn, R. Jacobs, V. Vuksan, K. Teo, B. Davis, P. Montague, and S. Yusuf Relationship of Metabolic Syndrome and Fibrinolytic Dysfunction to Cardiovascular Disease Circulation, July 29, 2003; 108(4): 420 - 425. [Abstract] [Full Text] [PDF]
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M. F. Carroll and D. S. Schade Timing of Antioxidant Vitamin Ingestion Alters Postprandial Proatherogenic Serum Markers Circulation, July 8, 2003; 108(1): 24 - 31. [Abstract] [Full Text] [PDF]
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 K.-H. Mak and D. P. Faxon Clinical studies on coronary revascularization in patients with type 2 diabetes Eur. Heart J., June 2, 2003; 24(12): 1087 - 1103. [Abstract] [Full Text] [PDF]
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S. Devaraj, D. Y. Xu, and I. Jialal C-Reactive Protein Increases Plasminogen Activator Inhibitor-1 Expression and Activity in Human Aortic Endothelial Cells: Implications for the Metabolic Syndrome and Atherothrombosis Circulation, January 28, 2003; 107(3): 398 - 404. [Abstract] [Full Text] [PDF]
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S. Konstantinides, K. Schafer, and D. J. Loskutoff Do PAI-1 and Vitronectin Promote or Inhibit Neointima Formation?: The Exact Role of the Fibrinolytic System in Vascular Remodeling Remains Uncertain Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1943 - 1945. [Full Text] [PDF]
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 W. T. Cefalu, D. J. Schneider, H. E. Carlson, P. Migdal, L. Gan Lim, M. P. Izon, A. Kapoor, A. Bell-Farrow, J. G. Terry, and B. E. Sobel Effect of Combination Glipizide GITS/Metformin on Fibrinolytic and Metabolic Parameters in Poorly Controlled Type 2 Diabetic Subjects Diabetes Care, December 1, 2002; 25(12): 2123 - 2128. [Abstract] [Full Text] [PDF]
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A. I. Vulin and F. M. Stanley A Forkhead/Winged Helix-related Transcription Factor Mediates Insulin-increased Plasminogen Activator Inhibitor-1 Gene Transcription J. Biol. Chem., May 31, 2002; 277(23): 20169 - 20176. [Abstract] [Full Text] [PDF]
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R. H. Eckel, M. Wassef, A. Chait, B. Sobel, E. Barrett, G. King, M. Lopes-Virella, J. Reusch, N. Ruderman, G. Steiner, et al. Prevention Conference VI: Diabetes and Cardiovascular Disease: Writing Group II: Pathogenesis of Atherosclerosis in |