(Circulation. 1996;93:1073-1078.)
© 1996 American Heart Association, Inc.
Articles |
Angiotensin-Converting Enzyme Inhibition Suppresses Plasminogen Activator Inhibitor-1 Expression in the Neointima of Balloon-Injured Rat Aorta
From the Research Division of the Joslin Diabetes Center (J.B.G., A.D.H., E.P.F.) and the Departments of Vascular Surgery (A.D.H., W.C.Q.) and Pathology (W.C.Q.), Deaconess Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Edward P. Feener, PhD, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail FEENERE@Joslab.Harvard.EDU.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Plasminogen activator inhibitor-1 (PAI-1), an important regulator of fibrinolysis and extracellular matrix turnover, has been implicated in a number of vascular diseases. Studies demonstrating angiotensin II (Ang II) to be a potent stimulator of PAI-1 expression in cultured vascular cells suggests that the renin-angiotensin system may modulate vascular PAI-1 expression.
Methods and Results We examined the effects of the ACE inhibitor captopril on PAI-1 expression in control and balloon-injured rat aorta. Northern blot analysis demonstrated that aortic PAI-1 mRNA expression was 7.6-fold elevated 3 hours (P<.05) after balloon injury, back to baseline at 2 days, increased again at 4 days, and by 7 days after balloon injury was 3.2-fold elevated (P<.05) when compared with control. In captopril-treated rats, the induction of PAI-1 expression by balloon injury was significantly suppressed by 44% (P<.05) in the 7-day group but was not altered in the 3-hour group. Captopril also reduced baseline aortic PAI-1 mRNA. In situ hybridization and immunohistochemistry revealed dense PAI-1 staining of 7-day neointima in untreated rats and a dramatic decrease in PAI-1 in neointima of captopril-treated rats.
Conclusions This report demonstrates that balloon injury results in both a rapid ACE inhibitor–independent induction of aortic PAI-1 expression and a later increase in PAI-1 in the neointima that is significantly suppressed by captopril. This provides the first evidence that the renin-angiotensin system regulates neointimal PAI-1 expression and that ACE inhibitors can reduce PAI-1 in the vessel wall in vivo.
Key Words: plasminogen • angiotensin • aorta • balloon • catheterization
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Plasminogen activator inhibitor-1 (PAI-1) is a key regulator of plasmin-mediated proteolytic cascades, which contribute to both fibrinolysis and extracellular matrix turnover.1 2 It exerts a negative influence on fibrinolysis and matrix degradation through inhibition of tissue plasminogen activator and urokinase plasminogen activator, respectively. Elevated levels of PAI-1, via inhibition of these proteolytic cascades, have been implicated in contributing to thrombosis and altered vessel wall architecture in a number of vascular diseases. Increased plasma PAI-1 is observed in patients who develop restenosis after angioplasty3 and has been proposed as a possible risk factor for myocardial infarction.4 5 6 In addition, increased PAI-1 expression was noted in the thickened intima at the base of human atherosclerotic plaques,7 8 and balloon injury was demonstrated to increase PAI-1 levels in the plasma and carotid arteries of rabbits by as early as 3 hours.9 10 Since PAI-1 plays an inhibitory role in matrix turnover and fibrinolysis, increased levels of PAI-1 in the vascular wall could contribute to local accumulation of extracellular matrix and fibrin deposits. Although the regulation of PAI-1 expression in cultured vascular cells has been studied extensively, and it has been shown in vivo that exogenously delivered tumor necrosis factor-
and
transforming growth factor-ß induce tissue-specific increases in
PAI-1 mRNA,11 little is known about the specific factors
that regulate expression of PAI-1 in the vascular wall in vivo. Recent experimental and clinical studies have suggested that the renin-angiotensin system may be an important regulator of PAI-1 expression. Angiotensin II (Ang II) has been shown to be a potent stimulator of PAI-1 expression in cultured vascular smooth muscle cells and endothelial cells.12 13 14 Infusion of Ang II has been shown to rapidly increase plasma PAI-1 levels.15 While increased PAI-1 expression and levels have been associated with both myocardial infarction and atherosclerosis,4 7 8 the mechanisms that contribute to these increases in PAI-1 are unknown. Clinical reports have demonstrated that ACE inhibition significantly reduces the risk of recurrent myocardial infarction,16 whereas in the case of acute myocardial infarction, ACE inhibitors given within 1 day of the event resulted in a decrease in both early (<24 hours) and long-term mortality.17 18 While this may suggest a link between the vascular renin-angiotensin system and alteration in fibrinolysis, direct evidence for such an interaction has not been reported.
Previous studies with ACE inhibitors as well as Ang II receptor antagonists have demonstrated that the renin-angiotensin system contributes to the development of the neointima seen after balloon injury of the carotid artery and aorta.19 20 Examination of the vascular renin-angiotensin system after balloon injury has revealed increases in angiotensinogen mRNA, Ang II type I receptor, and ACE activity in the developing neointima.21 22 23 Since these reports demonstrated that balloon injury results in an activation of the renin-angiotensin system, we used this model to test the role of an ACE inhibitor on the in vivo regulation of PAI-1 expression in the aortic wall. This study revealed an induction of aortic PAI-1 mRNA expression 3 hours after balloon injury, a subsequent return to baseline levels at 2 days, and another significant increase in expression 7 days after injury. The increase in PAI-1 mRNA expression at 3 hours after balloon injury was not suppressed by captopril treatment. However, the induction of PAI-1 expression 7 days after injury (localized to the neointima) as well as baseline aortic PAI-1 expression was significantly suppressed by treatment with captopril. These results suggest that the renin-angiotensin system regulates PAI-1 expression in the developing neointima and provides the first evidence that ACE inhibitors can reduce PAI-1 mRNA in the vessel wall in vivo.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Balloon Catheter–Induced Injury
Male Sprague-Dawley rats (weight, 300 g) were obtained from Taconic Farms (Germantown, NY). Care of the animals complied with the rules and regulations of the Committee on Ethics and Animal Research at the Joslin Diabetes Center. Animals in captopril-treated groups that underwent balloon injury were housed singly and treated with 1 mg/mL of captopril (Sigma Chemical Co) freshly dissolved in the drinking water, as described previously.19 20 Nonsurgical animals either received 1 mg or 1.5 mg/mL as indicated. Rats were anesthetized with continuous methoxyflurane, with the right iliac artery isolated. As described previously, an arteriotomy was made, and a 2F Fogarty embolectomy catheter (Baxter Healthcare Corp) was passed proximally into the thoracic aorta, distended, and pulled back to the bifurcation.20 24 25 This was repeated three times. In the sham-operative control, for all groups except the 3-hour group, the iliac artery was ligated but there was no balloon denudation. In the 3-hour group, the sham consisted of catheter passage without balloon inflation. All animals underwent aortic harvest after the appropriate interval by inhalation of CO2. Rats in captopril groups that did not undergo balloon injury received the drug for 6 days, while those that underwent balloon injury with captopril were dosed for 4 days before procedure and through to the time they were killed.
Total RNA Isolation and Northern Blot
Analysis
The thoracic aorta and a portion of the abdominal aorta were
included in the tissue specimens. PAI-1 mRNA expression was examined by
Northern blot analysis with 10 to 20 µg total RNA, as
described previously.12 The signals were visualized and
quantitated by a phosphorimager (Molecular Dynamics). To normalize for
possible lane loading differences, blots were rehybridized with 36B4, a
constitutively regulated mRNA whose expression has been previously
shown to remain unchanged after various stimuli including Ang
II.12 26
Histology
At the time of aortic harvest, a 3-mm segment of
abdominal aorta
5 mm proximal to the renal arteries was fixed in 10% neutral buffered
formalin. The specimens were then processed by standard
histological techniques for light microscopy, in situ
hybridization, and immunohistochemical evaluation.
In Situ Hybridization
Bluescript KS-
containing the cDNA for rat
PAI-112 was linearized to produce sense and antisense
templates. Digoxigenin-UTP–labeled riboprobes were generated with T3
and T7 RNA polymerase (Boehringer Mannheim). In situ
hybridization of tissue sections affixed to Plus slides (Fisher
Scientific) was performed on an automated immunostainer
(Ventanna Medical Systems) per standard nonisotopic
techniques.27 After hybridization, alkaline
phosphatase–conjugated antidigoxigenin antibody was applied and
detection accomplished with nitro blue
tetrazolium/5-bromo-4-chloro-3-indolyl phosphate as a substrate.
Immunohistochemistry
Duplicate sections of those used in in
situ hybridization were
deparaffinized and hydrated to water. Primary antibody against rat
PAI-1 (American Diagnostica Inc) was diluted 1:200 and
applied to sections for 1 hour. After PBS rinses, secondary antibody
was applied (goat anti-rabbit) and the signal detected with
diaminobenzidine. Negative controls received the same treatment, except
nonimmune serum was used in place of primary antibody.
Statistical Analysis
The unpaired Student's t
test was used for
comparison of hemodynamic parameters.
Statistical differences between several groups were determined with
one-way ANOVA and the Mann-Whitney rank sum test.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Characteristics of Sprague-Dawley Rats
Hemodynamic parameters were evaluated with a rat tail plethysmograph (Ueda Electronics) 1 day before the rats were killed. The mean blood pressure and heart rate, after 5 days of captopril treatment, were 115±12.8 mm Hg (mean±SD) and 426±46.3 beats per minute (bpm) (n=13), 109±10.2 mm Hg and 461±28.7 bpm (n=11), and 104±7.7 mm Hg and 441±29.6 bpm (n=4) in the control, 1 mg/mL, and 1.5 mg/mL captopril groups, respectively. The differences among these groups were not statistically significant.
Effect of Captopril on PAI-1 mRNA Expression in Rat
Aorta
The level of PAI-1 mRNA expression in whole aorta was quantified
with Northern blot analysis. Aortic PAI-1 mRNA expression in
the nonsurgical animals, normalized to 36B4, was 6.07±0.59 (arbitrary
units, mean±SEM, n=40) in control rats and 6.13±1.14
(n=22) in
rats treated with 1 mg/mL captopril. However, in rats treated with 1.5
mg/mL captopril, PAI-1 expression was significantly decreased to
2.58±0.62 (n=4, P<.05).
The effect of balloon
injury with or without captopril treatment on
aortic PAI-1 expression was examined at 3 hours and at 2, 4, and 7 days
after surgery. Aortic PAI-1 mRNA levels, normalized to 36B4 expression,
were 7.6-fold elevated (P<.05) 3 hours after balloon injury
(n=4) when compared with control (n=3) and 3.1-fold increased
(P<.05) when compared with sham-operated rats (n=3) in
which a noninflated balloon catheter was passed into the aorta (Fig
1
). This early induction of PAI-1 mRNA was not affected
by captopril treatment (n=4) (Fig 1). Two days after
balloon injury
(n=3), PAI-1 mRNA expression had returned to baseline levels and was
not altered by captopril treatment (n=3) (Fig 2B). After
4 days, balloon injury appeared to induce a small increase in PAI-1
mRNA that was suppressed with captopril; however, these changes were
not statistically significant (n=3 for each group) (Fig
2B). PAI-1 mRNA
expression was significantly increased by 3.2-fold (P<.05)
in the 7-day injury group (n=4) when compared with the nonsurgical
control (Fig 2), a second phase of balloon injury–induced
PAI-1
expression. Moreover, PAI-1 mRNA levels in the 7-day balloon injury
group were also significantly greater than PAI-1 levels in the
sham-operated and 2-day balloon injury group (P<.05)
(Fig 2A). In the 7-day balloon injury group treated with
captopril
(n=4), the induction of PAI-1 mRNA levels was significantly reduced by
44% (P<.05) compared with the untreated 7-day balloon
injury group (Fig 2). In addition, PAI-1 mRNA levels in the
7-day
balloon injury group that received captopril were not significantly
elevated when compared with the nonsurgical controls (Fig 2B).
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Histological examination of aortic specimens revealed
that at 3 hours and at 2 days after balloon injury, there was
endothelial denudation and partial stretch injury to
the media (not shown). Four days after balloon injury, smooth muscle
cells were observed past the internal elastic lamina (not shown), and
after 7 days, there was a developing cellular neointima
(Fig 3B), as described
previously.24 25 As
noted previously, the size of the neointima was diminished
in captopril-treated animals (Fig
3C).19 20
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In Situ Hybridization and Immunohistochemistry of PAI-1 in Rat
Aorta With or Without Captopril
In situ hybridization was performed on
duplicate tissue sections
with antisense and sense RNA probes for rat PAI-1 labeled with
digoxigenin-UTP. Antisense staining in the control aorta was scant,
with some signal in intimal endothelial cells and in
smooth muscle cells of the aortic media (Fig 3D
). When aortic
sections
from 7-day balloon injury groups were probed with antisense for PAI-1,
there was dense signal localized to the neointima as
described previously9 (Fig 3E). In the 7-day
injury group
treated with captopril, antisense staining for PAI-1 in the remaining
neointima was dramatically decreased when compared with the
matched aortas not treated with captopril (Fig 3E and
3F). When
duplicate sections were probed with sense, minimal background staining
was observed (Fig 3, G through I). Immunohistochemistry with
the use of
an anti–PAI-1 antibody revealed that PAI-1 protein levels in the
neointima correlated with PAI-1 mRNA expression at 7 days
(Fig 3K and 3L). No change in PAI-1 protein
levels was detected at 3
hours after injury (not shown), probably because of the longer time
interval required for de novo PAI-1 protein synthesis. Negative
controls (not shown) given nonimmune serum and the same detection
antibody revealed only minimal staining. Results are
representative of multiple sections from at least two
rats in each group.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In this report, we have demonstrated that the ACE inhibitor captopril can suppress induction of PAI-1 expression in the neointima after balloon injury. This in vivo finding is consistent with results from previous studies showing induction of components of the vascular renin-angiotensin system after balloon injury21 22 23 and Ang II to be a potent stimulator of PAI-1 expression in cultured vascular cells.12 13 14 In addition, a 50% greater dose of captopril than that used in the balloon injury group significantly decreased PAI-1 expression in the normal vessel. Collectively, these results strongly indicate that the renin-angiotensin system contributes to the regulation of vascular PAI-1 expression but is not the only mechanism, since captopril does not suppress the very early induction of PAI-1 (3 hours) after balloon injury. This report is the first direct evidence of a specific factor, captopril, which suppresses both baseline and neointimal PAI-1 mRNA expression in the vessel wall.
Evaluation of PAI-1 expression in balloon-injured rat aorta
revealed a significant increase at 3 hours, followed by a return to
baseline levels at 2 days and a secondary increase in PAI-1 levels 7
days after injury. The later increase in PAI-1 expression correlates
with data from previous studies revealing upregulation of components of
the renin-angiotensin system in the
neointima after balloon injury22 23 and more
specifically that the peak for balloon catheter–induced
angiotensinogen gene expression in the aorta was 7 days
after injury.21 It appears that development of a
neointima may be necessary for the later increase in PAI-1,
since balloon injury and surgical stress alone did not produce an
induction of PAI-1 at a time interval (2 days) before the presence of a
neointima. The early induction in PAI-1 was similar to that
observed by Sawa et al9 in balloon-injured rabbit
carotid arteries. Our finding that captopril treatment did not suppress
this rapid increase in PAI-1 mRNA suggests that acutely after injury,
mechanism(s) other than the renin-angiotensin system
are involved. Also, the data demonstrating a significant increase in
PAI-1 mRNA at 3 hours by passage of the balloon catheter without
inflation alone (sham) (Fig 1A and 1B), suggest
that during this early
period, a component of the vascular PAI-1 induction is not due to the
denudation injury of the vessel. In addition, we found that control
aortic PAI-1 expression can be significantly decreased by captopril,
suggesting that in the quiescent vessel, the
renin-angiotensin system plays a role in baseline PAI-1
expression.
Localization of mRNA expression using in situ hybridization with antisense probe for PAI-1 revealed a low level of expression in the control aorta. In the 7-day balloon injury group, there was a dramatic increase in PAI-1 signal with specific localization to the developing neointima, as seen previously.9 In the 7-day balloon-injured rats treated with captopril, staining of PAI-1 within the remaining neointima was dramatically reduced. Thus, captopril appeared to reduce the level of PAI-1 expression in the neointimal cells. These changes in PAI-1 expression in the neointima were also detected at the protein level by immunohistochemistry with an anti–PAI-1 antibody. We speculate that the suppression of PAI-1 in the neointima by captopril treatment may result in enhanced luminal fibrinolysis and extracellular matrix turnover.
Although our study provides evidence that ACE inhibitors regulate neointimal PAI-1 expression, and previous reports have demonstrated ACE inhibitors to reduce neointimal thickening in the balloon-injured vasculature of both rats and rabbits,19 20 28 the MERCATOR Study Group did not find ACE inhibitors to be protective against restenosis after angioplasty.29 A number of factors need to be considered, however, when comparing experimental studies in rats or rabbits with clinical studies of human coronary angioplasty. These factors include ACE inhibitor dose, species, type of vessel, level of preexisting atherosclerosis, presence of other medications, and the occurrence of concomitant disorders such as diabetes. Nevertheless, both the present study and previous reports demonstrating Ang II to be a potent stimulator of PAI-1 expression in cultured vascular cells12 13 14 suggest that the renin-angiotensin system contributes to the regulation of vascular PAI-1 expression.
While we and others have shown that Ang II–induced PAI-1 expression in cultured vascular cells is mediated via Ang II receptors,12 14 a recent report suggests that an angiotensin IV (Ang IV) receptor also may be involved in PAI-1 expression in cultured endothelial cells from large blood vessels.30 Since ACE inhibitors block the production of both Ang II and the hexapeptide Ang IV, contributions from both receptor pathways would be expected to be inhibited by captopril. Further studies with specific angiotensin receptor antagonists are needed to evaluate the role of both the Ang II and the Ang IV receptor pathways in the regulation of vascular PAI-1 expression in vivo.
This report demonstrates that the renin-angiotensin system contributes to the regulation of PAI-1 expression in normal and balloon-injured aortic wall of rats. After balloon injury, captopril suppresses the expression of PAI-1 in the cells of the developing neointima. This action could be of benefit in reducing local thrombosis or matrix accumulation at a site of vascular injury. In conclusion, this study provides the first evidence that the ACE inhibitor captopril can suppress vascular PAI-1 expression.
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Acknowledgments |
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This work was supported by Harvard-Longwood Research Training in Vascular Surgery, NIH, T32HL07734-02 (A.D.H.), NIH grant DK48358 (E.P.F.), a Juvenile Diabetes Foundation Research Award (E.P.F.), and NIH Diabetes and Endocrinology Research Center grant 36836.
Received December 11, 1995; accepted January 3, 1996.
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 N. J. Brown, L. J. Murphey, N. Srikuma, N. Koschachuhanan, G. H. Williams, and D. E. Vaughan Interactive Effect of PAI-1 4G/5G Genotype and Salt Intake on PAI-1 Antigen Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 1071 - 1077. [Abstract] [Full Text] [PDF]
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 L. Sironi, A. M. Calvio, L. Arnaboldi, A. Corsini, A. Parolari, M. de Gasparo, E. Tremoli, and L. Mussoni Effect of Valsartan on Angiotensin II-Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells Hypertension, March 1, 2001; 37(3): 961 - 966. [Abstract] [Full Text] [PDF]
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 K. Lottermoser, H.-J. Hertfelder, M. Wehling, B. Schiermeyer, H. Vetter, and R. Dusing Effects of the mineralocorticoid fludrocortisone on fibrinolytic function in healthy subjects Journal of Renin-Angiotensin-Aldosterone System, December 1, 2000; 1(4): 357 - 360. [Abstract] [PDF]
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H.-C. Chen, J. L. Bouchie, A. S. Perez, A. C. Clermont, S. Izumo, J. Hampe, and E. P. Feener Role of the Angiotensin AT1 Receptor in Rat Aortic and Cardiac PAI-1 Gene Expression Arterioscler Thromb Vasc Biol, October 1, 2000; 20(10): 2297 - 2302. [Abstract] [Full Text] [PDF]
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D. E. Vaughan AT1 Receptor Blockade and Atherosclerosis : Hopeful Insights Into Vascular Protection Circulation, April 4, 2000; 101(13): 1496 - 1497. [Full Text] [PDF]
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J. L. Bouchie, H.-C. Chen, R. Carney, J. C. Bagot, P. A. Wilden, and E. P. Feener P2Y Receptor Regulation of PAI-1 Expression in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, March 1, 2000; 20(3): 866 - 873. [Abstract] [Full Text] [PDF]
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 J. W. Sayer, C. Gutteridge, D. Syndercombe-Court, P. Wilkinson, and A. D. Timmis Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors J. Am. Coll. Cardiol., December 1, 1998; 32(7): 1962 - 1968. [Abstract] [Full Text] [PDF]
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N. J. Brown, M. A. Agirbasli, G. H. Williams, W. R. Litchfield, and D. E. Vaughan Effect of Activation and Inhibition of the Renin-Angiotensin System on Plasma PAI-1 Hypertension, December 1, 1998; 32(6): 965 - 971. [Abstract] [Full Text] [PDF]
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J. L. Bouchie, H. Hansen, and E. P. Feener Natriuretic Factors and Nitric Oxide Suppress Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells : Role of cGMP in the Regulation of the Plasminogen System Arterioscler Thromb Vasc Biol, November 1, 1998; 18(11): 1771 - 1779. [Abstract] [Full Text] [PDF]
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M. Margaglione, G. Cappucci, M. d'Addedda, D. Colaizzo, N. Giuliani, G. Vecchione, G. Mascolo, E. Grandone, and G. Di Minno PAI-1 Plasma Levels in a General Population Without Clinical Evidence of Atherosclerosis : Relation to Environmental and Genetic Determinants Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 562 - 567. [Abstract] [Full Text] [PDF]
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D.-K. Kim, J.-W. Kim, S. Kim, H.-C. Gwon, J.-C. Ryu, J.-E. Huh, J.-A Choo, Y. Choi, C.-H. Rhee, and W.-R. Lee Polymorphism of Angiotensin Converting Enzyme Gene Is Associated With Circulating Levels of Plasminogen Activator Inhibitor-1 Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 3242 - 3247. [Abstract] [Full Text]
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D. E. Vaughan, J.-L. Rouleau, P. M. Ridker, J. M. O. Arnold, F. J. Menapace, and M. A. Pfeffer Effects of Ramipril on Plasma Fibrinolytic Balance in Patients With Acute Anterior Myocardial Infarction Circulation, July 15, 1997; 96(2): 442 - 447. [Abstract] [Full Text]
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