(Circulation. 2001;103:276.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
An HMG-CoA Reductase Inhibitor, Cerivastatin, Suppresses Growth of Macrophages Expressing Matrix Metalloproteinases and Tissue Factor In Vivo and In Vitro
From the Cardiovascular Division, Department of Medicine (M.A., S.S., S.J.V., Y. Fukumoto, Y. Furukawa, P.L.) and Department of Pathology (E.R., F.J.S.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass, and Institute for Experimental Animals, Kobe University School of Medicine (M.S.), Kobe, Japan.
Correspondence to Masanori Aikawa, MD, PhD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 309, Boston, MA 02115. E-mail maikawa{at}rics.bwh.harvard.edu
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Abstract |
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Background—Unstable atherosclerotic plaques that cause acute coronary events usually contain abundant macrophages expressing matrix metalloproteinases (MMPs) and tissue factor (TF), molecules that probably contribute to plaque rupture and subsequent thrombus formation. Lipid lowering with HMG-CoA reductase inhibitors reduces acute coronary events.
Methods and Results—To
test whether lipid lowering with an HMG-CoA reductase inhibitor retards
macrophage accumulation in rabbit atheroma, we administered
cerivastatin to immature Watanabe heritable hyperlipidemic rabbits
(cerivastatin group, n=10, cerivastatin 0.6
mg · kg-1 · d-1;
control group, n=9, saline 0.6
mL · kg-1 · d-1)
for 32 weeks and measured macrophage accumulation and expression of
MMPs and TF. Serum cholesterol levels after 32 weeks were 809±40 mg/dL
(control group) and 481±24 mg/dL (treated group). Cerivastatin
diminished accumulation of macrophages in aortic atheroma. Macrophage
expression of MMP-1, MMP-3, MMP-9, and TF also decreased with
cerivastatin treatment. Cerivastatin reduced the number of macrophages
expressing histone mRNA (a sensitive marker of cell proliferation)
detected by in situ hybridization but did not alter macrophages bearing
a marker of death (TUNEL staining). Cerivastatin treatment (
0.01
µmol/L) also reduced growth, proteolytic activity due to MMP-9, and
TF expression in cultured human
monocyte/macrophages.
Conclusions—These results suggest that lipid lowering with HMG-CoA reductase inhibitors alters plaque biology by reducing proliferation and activation of macrophages, prominent sources of molecules responsible for plaque instability and thrombogenicity.
Key Words: atherosclerosis • inflammation • thrombosis • hypercholesterolemia • metalloproteinases
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Atherosclerotic plaques prone to rupture, thrombus formation, and consequent acute coronary events frequently contain a prominent accumulation of inflammatory cells, including macrophages.1 2 3 Macrophages in atheroma overexpress matrix metalloproteinases (MMPs), such as MMP-1 (collagenase-1), MMP-3 (stromelysin-1), and MMP-9 (gelatinase-B).4 5 6 Lesional macrophages also express tissue factor (TF), a strong activator of blood coagulation, as well as its inducer CD40 ligand (CD40L or CD154).7 8 Overexpression of such matrix-degrading enzymes and prothrombotic molecules most likely contributes to plaque instability and thrombogenicity.9 10 Thus, the macrophage content of an atheroma can critically influence its clinical consequences.
Several mechanisms regulate macrophage accumulation in plaques. Endothelial cells in atheroma overexpress molecules that contribute to monocyte recruitment.11 Survival factors such as macrophage-colony–stimulating factor (M-CSF) promote persistence of these cells in plaques.12 Macrophage proliferation may also participate in the formation of vulnerable atheroma rich in this cell type.13 14 15 M-CSF, granulocyte macrophage-CSF (GM-CSF), and oxidized LDL, each of which accumulates in atheroma, can induce macrophage proliferation in vitro.16 17 18
Cholesterol lowering with inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase inhibitors) reduces the incidence of acute coronary events in patients, probably by functional changes of atheroma ("stabilization").19 20 21 We have recently demonstrated that dietary lipid lowering in cholesterol-fed rabbits reduces expression and activity of MMPs and TF in established atheroma by reducing macrophage number and, in turn, ameliorating smooth muscle cell (SMC) activation.22 23 24 These experiments, although informative, used a model of exogenous hypercholesterolemia and an intervention that produced a greater degree of lipid lowering than clinically practicable. Also, these experiments evaluated the effects of lipid lowering on existing lesions. Moreover, many recent studies have involved possible effects of the HMG-CoA reductase inhibitors beyond their lipid-lowering actions.25 We therefore tested cerivastatin, a potent novel HMG-CoA reductase inhibitor,26 on new lesion development in Watanabe heritable hyperlipidemic (WHHL) rabbits that have endogenous hypercholesterolemia due to LDL receptor deficiency. Shiomi et al27 demonstrated that cerivastatin retards progression of atherosclerosis in terms of plaque size and macrophage accumulation in WHHL rabbits. We report here an extension of this study on WHHL rabbits designed to test the hypothesis that cerivastatin can prevent macrophage expression of molecules responsible for plaque disruption and thrombus formation. We also determined whether cerivastatin reduces macrophage growth both in vivo and in vitro as a potential mechanism of reduced macrophage accumulation.
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Methods |
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Animal Experiment
The protocol of this experiment has been described in detail.27 Nineteen WHHL rabbits at 2 months of age were housed individually in metal cages and were fed a regular laboratory diet. Cerivastatin solution (Bayer Yakuhin) was administered to the animals of the cerivastatin group (n=10, 0.6 mg · kg-1 · d-1 SC) for 32 weeks. The animals of the control group received saline (n=9, 0.6 mL · kg-1 · d-1 SC) for 32 weeks. All animal experiments were performed in accordance with the Guidelines for Animal Experimentation of the Kobe University School of Medicine.
Tissue Sampling
The aortic tissues were excised 2 mm above the
ligamentum arteriosum and snap-frozen or fixed with 4%
paraformaldehyde. Surgical specimens of human carotid plaques were
obtained in accordance with a protocol approved by the Human
Investigation Review Committee at Brigham and Women’s
Hospital.
Histochemical Assays
Immunohistochemistry was performed by the ABC method
(Vector).22 23 24
Antibodies included mouse monoclonal antibodies against rabbit CD11b
(Spring Valley), human 
-smooth muscle actin (1A4, Dako), human
MMP-1, rabbit MMP-3, human MMP-9 (Calbiochem), rabbit TF (American
Diagnostica), and a rat monoclonal antibody for mouse CD40L (a gift
from Immunex; Seattle, Wash). For a negative control, nonimmune
IgG was applied in place of antibodies. Picrosirius red polarization
was performed to detect interstitial collagen content according to
Junqueira’s method as modified by
us.22 Nonisotopic in situ
hybridization for histone mRNA was performed with the Hyb-Probe
Detection System (Shandon/Lipshaw) as previously
described.24 Briefly,
sections of rabbit and human atheroma and cultured human macrophages
(day 7) were fixed briefly with 4% paraformaldehyde and hybridized
with fluorescein-labeled oligonucleotide cocktail for histone mRNAs and
random oligomers (negative control). mRNA signals were detected by
alkaline phosphatase–conjugated antibody against FITC.
Immunohistochemistry for CD11b, CD68, and -actin was then performed.
Terminal deoxynucleotidyl transferase (TdT)–mediated dUTP nick
end-labeling (TUNEL) staining was performed according to the
manufacturer’s instructions on 4% paraformaldehyde–fixed paraffin
sections (Intergen). As a negative control, oligonucleotides were
applied without TdT. Immunohistochemistry for CD11b was then performed.
Quantitative analysis of immunohistochemistry and picrosirius red
staining used a computer-assisted color image analysis
system.22 23 24
For in situ hybridization and TUNEL staining, positive macrophages in
the intima were counted manually by 2 independent
investigators.
In Vitro Experiments
Human monocytes were obtained from human peripheral
blood by density gradient centrifugation and adherence. Monocytes were
plated at 5x106 cells/well on 6-well plates
in M199 medium containing 2% human serum and 200 U/mL M-CSF (a gift
from Genetics Institute; Cambridge, Mass) and cultured for 10 days with
and without cerivastatin. The cell numbers were measured by both manual
counting and MTS
[3-(4.5-dimethythiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium]
assay (Promega). M-CSF–induced replication was determined on
day 10 macrophages with an ELISA for bromodeoxyuridine (BrdU, Roche)
incorporation. Immunocytochemistry using peroxidase-conjugated
anti-BrdU antibody detected BrdU uptake by macrophages.
Monocyte/macrophages at days 1 and 10 were used for gelatin
zymography.22 Culture medium
was changed 24 hours before zymography. The amount of culture medium
applied for the gel electrophoresis was adjusted on the basis of the
cell number. FITC-conjugated mouse monoclonal anti–human TF antibody
(American Diagnostica) was used for fluorescence-activated cell sorter
(FACS) analysis.
Statistical Analysis
Statistical testing for quantification of
histochemical assays used the Mann-Whitney
U test. One-way ANOVA followed
by the post hoc test was used for in vitro
assays.
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Results |
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Lipid Profile
Plasma lipid analysis on these animals has already been reported.27 Briefly, the mean total cholesterol, triglyceride, and phospholipid levels (mg/dL) of the 2 groups were similar at the beginning of the experiment. At 32 weeks, we observed a statistically significant reduction in total cholesterol levels in the cerivastatin group (481±24 mg/dL) versus the control group (809±40 mg/dL). Phospholipid levels also decreased (447±22 and 318±24 mg/dL, respectively), but there was no significant difference in triglyceride levels (228±23 and 183±12 mg/dL, respectively).
Effects of Cerivastatin on MMP and TF in
Atheroma
Atheroma of WHHL rabbits treated with saline for
32 weeks contained many macrophages (CD11b-positive cells)
(Figure 1A
). Immunoreactive MMP-1, MMP-3, and MMP-9
colocalized with macrophages. However, the areas immunopositive for
CD11b (mm2) decreased in the cerivastatin
group, determined by quantitative color image analysis
(Figures 1B and 2A). We further quantified MMP-positive areas
within macrophage-containing regions
(Figure 2B, 2C, and 2D). The data suggest decreased
macrophage expression of MMP-1, MMP-3, or MMP-9 by cerivastatin
treatment. Picrosirius red polarization was performed to determine
whether increased accumulation of interstitial collagen paralleled
reduced matrix-degrading enzymes. Aortas from the control group showed
intense staining in the adventitia and relatively weak staining in the
intima and the media
(Figure 3A). However, the aortic intimas from the
cerivastatin group showed more intense staining than those from the
control group
(Figure 3A). Quantitative analysis showed a 1.7-fold increase
in picrosirius red–positive intimal areas in the cerivastatin group
compared with the control group
(Figure 3B). The intima of the control group showed TF
expression that colocalized with its inducer, CD40L
(Figure 4A). Intimal TF expression of the cerivastatin group
was lower than that of the control group, in association with reduced
expression of CD40L
(Figure 4A). Quantitative analysis demonstrated that
cerivastatin significantly reduced the percentage of TF-positive
macrophages in the intima
(Figure 4B). Negative control applying nonimmune IgG in place
of the antibodies abrogated the staining (data not
shown).
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Effects of Cerivastatin on Proliferation and
Death of Macrophages in Atheroma
To address the potential mechanisms of reduced
macrophage number, we performed in situ hybridization for histone mRNA
(a sensitive marker for cell
proliferation)28 and TUNEL
staining for cell death. Based on the expression of histone mRNA, 9.0%
of macrophages showed this sign of replication in atheroma of the
control group. However, only 4.3% of macrophages stained positively
for histone mRNA in animals treated with cerivastatin
(Figures 5 and 7). No signal was detected with random
oligomers used as negative control (data not shown). In contrast, TUNEL
staining demonstrated that macrophages in both groups displayed similar
levels of DNA fragmentation characteristic of apoptotic cell death
(Figures 6 and 7). No positive signal was seen on the nuclei
without TdT reagent (data not shown).
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Effects of Cerivastatin on Macrophage Survival
and Proliferation In Vitro
In situ hybridization for histone mRNA detected
macrophage proliferation in human atheroma and verified the utility of
this technique for detection of proliferation of human macrophages as
well
(Figure 8). After 10-day culture with 200 U/mL of M-CSF and
2% human serum, human monocyte–derived macrophages expressed histone
mRNA and incorporated BrdU in their nuclei
(Figure 9). By either cell counting or MTS assay,
cerivastatin treatment (0.01 to 0.5 µmol/L) for 10 days significantly
reduced numbers of cultured human macrophages
(P<0.01)
(Figure 10A and 10B). BrdU incorporation by macrophages was
inhibited by 0.05 µmol/L of cerivastatin, an effect reversed by
coincubation with mevalonate, farnesyl pyrophosphate, or geranylgeranyl
pyrophosphate, suggesting that suppression of macrophage growth by
cerivastatin was achieved by inhibition of the mevalonate pathway, not
by cell injury or toxicity
(Figure 10C).
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) proliferation in human atheroma. In situ hybridization detected histone mRNA expression in intima of 2 samples of human carotid arteries. mRNA signals colocalized with macrophages detected by immunohistochemistry for CD68 on serial sections. Bar=50 µm. Magnification x400.
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Effects of Cerivastatin on MMP and TF In
Vitro
Gelatin zymography and FACS analysis tested whether
cerivastatin treatment affects macrophage production of MMP and TF, 2
functions inhibited by cerivastatin treatment in vivo. Gelatinolytic
activity at 92 kDa ascribable to MMP-9 rises in human macrophages at
day 10 compared with day 1 monocyte/macrophages. However, cerivastatin
treatment (0.05 µmol/L) prevented this increase, yielding levels
similar to those of monocyte/macrophages at day 1
(Figure 11A). Cerivastatin treatment (0.05 µmol/L) also
decreased TF expression in macrophages at day 10
(Figure 11B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Macrophages proliferate in human and hypercholesterolemic rabbit atheroma.13 14 15 29 Proliferation probably plays an important role in formation of macrophage-rich vulnerable plaques. Thus, inhibition of macrophage proliferation may promote stabilization of atheroma. M-CSF and GM-CSF induce macrophage survival and proliferation in vitro, and oxidized LDL enhances their action.12 16 17 18 Reduced oxidized LDL accumulation and GM-CSF and M-CSF expression in atheroma due to lowered LDL levels might suppress macrophage proliferation.30 The present study used in situ hybridization for histone mRNA28 31 to measure proliferation of macrophages in atheroma of WHHL rabbits. Histone mRNAs increase (
15-fold) in cells in S phase and decrease
immediately after cells leave S phase because they lack polyA
tails.28 32 Lipid
lowering by cerivastatin in this study (40.5% reduction in total
cholesterol) reduced the number of macrophages expressing histone mRNAs
in atheroma of WHHL rabbits. We recently found that dietary lipid
lowering reduces oxidized LDL accumulation in atheroma of
cholesterol-fed rabbits (M.A., et al, manuscript submitted). Such
improved oxidative stress might be one potential mechanism by which
cerivastatin treatment suppressed macrophage proliferation in rabbit
atheroma in the present study. We recently demonstrated that lipid lowering by diet alone can improve features typical of so-called unstable atheromatous plaques in rabbits.22 23 24 Thus, lipid lowering by dietary manipulation alone can ameliorate features of plaques associated with instability and thrombogenicity. Reaching target cholesterol levels in patients, however, often requires drug treatment in addition to diet. HMG-CoA reductase inhibitors decrease conversion of HMG-CoA into mevalonate, a precursor for endogenous cholesterol. The decreased cholesterol pool in cells in turn augments LDL-receptor levels on the cell surface, which lowers blood cholesterol levels. Thus, LDL-receptor deficiency limits this mechanism of cholesterol reduction by HMG-CoA reductase inhibitors. In this study of LDL receptor–deficient WHHL rabbits, the mean blood cholesterol levels of cerivastatin-treated animals still by far exceeded the normal range, unlike the dietary manipulation used in our previous rabbit studies.22 23 24 Nonetheless, cerivastatin treatment significantly reduced macrophage accumulation, despite persistent hypercholesterolemia. Cerivastatin suppresses SMC proliferation independently of its lipid-lowering effect.33 34 We therefore conjectured that cerivastatin has an antiproliferative effect on macrophages in addition to its lipid-lowering effect. To address this hypothesis, we determined the effects of cerivastatin on human monocyte–derived macrophages cultured with M-CSF. Cerivastatin (0.01 to 0.5 µmol/L) reduced macrophage number in a dose-dependent manner, suggesting that cerivastatin may suppress M-CSF–induced macrophage survival. Many previous in vitro demonstrations of the cellular effects of HMG-CoA reductase inhibitors have used doses that most likely exceed those encountered in patients. In the present study, 0.6 mg · kg-1 · d-1 of cerivastatin was administered to significantly decrease cholesterol levels of WHHL rabbits with an LDL-receptor deficiency. This dose was much higher than those used for humans. This is customary in animal studies, because much higher doses are required for statin effects than in humans. However, the level of cerivastatin effective in vitro (0.01 to 0.05 µmol/L) is close to peak plasma concentrations achieved in humans after a single oral administration of 300 to 800 µg of cerivastatin.35 36 Furthermore, effective doses of cerivastatin are lower than those of simvastatin and pravastatin required to retard growth of murine peritoneal macrophages induced by oxidized LDL (IC50 values, 0.7 and 70 µmol/L, respectively).37
The balance between proliferation and death in part determines the accumulation of cells in atheroma. This study demonstrates no significant difference in the number of macrophages bearing a marker of DNA fragmentation in the 2 groups, suggesting that cerivastatin treatment does not reduce macrophage accumulation by cell injury or apoptotic death. HMG-CoA reductase inhibitors can induce the death of cultured SMCs.38 Induction of death of SMCs in the fibrous cap by high doses of HMG-CoA reductase inhibitors may not be beneficial in terms of plaque stability, because SMCs synthesize extracellular matrix constituents, such as collagen, which strengthen plaques. Shiomi et al,27 interestingly, demonstrated that cerivastatin treatment reduced accumulation of macrophages, but not of SMCs, in atheroma of the same animals as used in this present study. Taken together, these results raise the possibility that certain doses of HMG-CoA reductase inhibitors can reduce accumulation of collagenolytic and prothrombotic macrophages in atheroma without inhibiting SMCs in the fibrous cap.
We show here that cerivastatin treatment reduced expression
of MMPs and TF in atheroma of WHHL rabbits. A decrease in the
percentage of macrophages expressing MMPs and TF in the cerivastatin
group suggests that reduced expression of such proteolytic or
prothrombotic molecules probably results from not only a diminished
number of macrophages but also a reduced macrophage activation
(Figure 2
). We studied these macrophage functions further in
vitro. Coincubation with cerivastatin (0.05 µmol/L) for 10 days
reduced proteolytic activity ascribable to MMP-9 and TF expression.
Bellosta et al39 and Colli
et al40 demonstrated similar
results on human macrophages in vitro with regard to reduced MMP-9
activity with fluvastatin treatment (5 to 100 µmol/L) and decreased
TF expression with fluvastatin (2.5 to 5 µmol/L) or simvastatin (2.5
µmol/L). These results suggest that HMG-CoA reductase inhibitors can
suppress not only proliferation but also activation of
macrophages.
Lipid lowering by HMG-CoA reductase inhibitors may alter the biology of atherosclerotic lesion formation. Among all vascular cell types, macrophages in particular are involved in all phases of atherosclerosis from initiation through progression and finally plaque rupture and thrombosis. This study demonstrated that cerivastatin can suppress the growth of macrophages that express proteolytic enzymes and a thrombogenic factor in atheroma of animals with endogenous hypercholesterolemia. Cerivastatin, in a concentration that can be achieved in patients, also suppresses proliferation and activation of macrophages in culture. This study provides new evidence for an effect of HMG-CoA reductase inhibitors on macrophage functions beyond lipid lowering and sheds new light on the mechanisms of plaque stabilization and reduced thrombotic complications in patients treated with HMG-CoA reductase inhibitors.
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Acknowledgments |
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This work was supported in part by NHLBI grant SCOR P50-HL-56985 and Merrit Award R37-HL-34636 (Dr Libby); Awards from the Japan Heart Foundation (Drs Aikawa and Furukawa), Uehara Foundation (Dr Sugiyama), and Kanae Foundation (Dr Fukumoto); and unrestricted educational and research gifts from Bayer Pharmaceuticals. We acknowledge Karen E. Williams, Elissa Simon-Morrisey, and Dmitriy Zvagelsky for their skillful assistance.
Received May 30, 2000; revision received July 14, 2000; accepted July 28, 2000.
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 F. Gungor, I. Kalelioglu, and A. Turfanda Vascular Effects of Estrogen and Progestins and Risk of Coronary Artery Disease: Importance of Timing of Estrogen Treatment Angiology, June 1, 2009; 60(3): 308 - 317. [Abstract] [PDF]
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 A. Gottsater, D. Flondell-Site, T. Kolbel, and B. Lindblad Associations Between Statin Treatment and Markers of Inflammation, Vasoconstriction, and Coagulation in Patients With Abdominal Aortic Aneurysm Vascular and Endovascular Surgery, January 1, 2009; 42(6): 567 - 573. [Abstract] [PDF]
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 S. Fujimoto, D. Hartung, S. Ohshima, D. S. Edwards, J. Zhou, P. Yalamanchili, M. Azure, A. Fujimoto, S. Isobe, Y. Matsumoto, et al. Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions: Resolution With Dietary Modification and Statin Therapy J. Am. Coll. Cardiol., December 2, 2008; 52(23): 1847 - 1857. [Abstract] [Full Text] [PDF]
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A. C. Newby Metalloproteinase Expression in Monocytes and Macrophages and its Relationship to Atherosclerotic Plaque Instability Arterioscler Thromb Vasc Biol, December 1, 2008; 28(12): 2108 - 2114. [Abstract] [Full Text] [PDF]
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 E J Hothersall, R Chaudhuri, C McSharry, I Donnelly, J Lafferty, A D McMahon, C J Weir, J Meiklejohn, N Sattar, I McInnes, et al. Effects of atorvastatin added to inhaled corticosteroids on lung function and sputum cell counts in atopic asthma Thorax, December 1, 2008; 63(12): 1070 - 1075. [Abstract] [Full Text] [PDF]
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S. Kinlay Vascular form and function: two mechanisms for cardiovascular prevention Eur. Heart J., July 2, 2008; 29(14): 1711 - 1713. [Full Text] [PDF]
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 T. T. Tuomisto, H. Lumivuori, E. Kansanen, S.-K. Hakkinen, M. P. Turunen, J. V. van Thienen, A. J. Horrevoets, A.-L. Levonen, and S. Yla-Herttuala Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2 Cardiovasc Res, April 1, 2008; 78(1): 175 - 184. [Abstract] [Full Text] [PDF]
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 E. Aikawa, M. Nahrendorf, J.-L. Figueiredo, F. K. Swirski, T. Shtatland, R. H. Kohler, F. A. Jaffer, M. Aikawa, and R. Weissleder Osteogenesis Associates With Inflammation in Early-Stage Atherosclerosis Evaluated by Molecular Imaging In Vivo Circulation, December 11, 2007; 116(24): 2841 - 2850. [Abstract] [Full Text] [PDF]
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I. Kosmidou, J. P. Moore, M. Weber, and C. D. Searles Statin Treatment and 3' Polyadenylation of eNOS mRNA Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2642 - 2649. [Abstract] [Full Text] [PDF]
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E. Fung, S.-M. T. Tang, J. P. Canner, K. Morishige, J. F. Arboleda-Velasquez, A. A. Cardoso, N. Carlesso, J. C. Aster, and M. Aikawa Delta-Like 4 Induces Notch Signaling in Macrophages: Implications for Inflammation Circulation, June 12, 2007; 115(23): 2948 - 2956. [Abstract] [Full Text] [PDF]
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S. Kinlay Low-Density Lipoprotein-Dependent and -Independent Effects of Cholesterol-Lowering Therapies on C-Reactive Protein: A Meta-Analysis J. Am. Coll. Cardiol., May 22, 2007; 49(20): 2003 - 2009. [Abstract] [Full Text] [PDF]
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 R. Gupta, L. C. Plantinga, N. E. Fink, M. L. Melamed, J. Coresh, C. S. Fox, N. W. Levin, and N. R. Powe Statin Use and Hospitalization for Sepsis in Patients With Chronic Kidney Disease JAMA, April 4, 2007; 297(13): 1455 - 1464. [Abstract] [Full Text] [PDF]
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S. J. Nicholls, E. M. Tuzcu, I. Sipahi, A. W. Grasso, P. Schoenhagen, T. Hu, K. Wolski, T. Crowe, M. Y. Desai, S. L. Hazen, et al. Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis JAMA, February 7, 2007; 297(5): 499 - 508. [Abstract] [Full Text] [PDF]
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E Hothersall, C McSharry, and N C Thomson Potential therapeutic role for statins in respiratory disease. Thorax, August 1, 2006; 61(8): 729 - 734. [Abstract] [Full Text] [PDF]
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J.-o Deguchi, M. Aikawa, C.-H. Tung, E. Aikawa, D.-E. Kim, V. Ntziachristos, R. Weissleder, and P. Libby Inflammation in Atherosclerosis: Visualizing Matrix Metalloproteinase Action in Macrophages In Vivo Circulation, July 4, 2006; 114(1): 55 - 62. [Abstract] [Full Text] [PDF]
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G. Stoll and M. Bendszus Inflammation and Atherosclerosis: Novel Insights Into Plaque Formation and Destabilization Stroke, July 1, 2006; 37(7): 1923 - 1932. [Abstract] [Full Text] [PDF]
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A. E. Silver and J. A. Vita Shear Stress-Mediated Arterial Remodeling in Atherosclerosis: Too Much of a Good Thing? Circulation, June 20, 2006; 113(24): 2787 - 2789. [Full Text] [PDF]
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T. Ohtani, Y. Ueda, I. Mizote, J. Oyabu, K. Okada, A. Hirayama, and K. Kodama Number of Yellow Plaques Detected in a Coronary Artery Is Associated With Future Risk of Acute Coronary Syndrome: Detection of Vulnerable Patients by Angioscopy J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2194 - 2200. [Abstract] [Full Text] [PDF]
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R. E. Tilley, B. Pedersen, R. Pawlinski, Y. Sato, J. H. Erlich, Y. Shen, S. Day, Y. Huang, D. T. Eitzman, W. A. Boisvert, et al. Atherosclerosis in Mice Is Not Affected by a Reduction in Tissue Factor Expression Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 555 - 562. [Abstract] [Full Text] [PDF]
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C. M. Dollery and P. Libby Atherosclerosis and proteinase activation Cardiovasc Res, February 15, 2006; 69(3): 625 - 635. [Abstract] [Full Text] [PDF]
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S. Ichihara, A. Noda, K. Nagata, K. Obata, J. Xu, G. Ichihara, S. Oikawa, S. Kawanishi, Y. Yamada, and M. Yokota Pravastatin increases survival and suppresses an increase in myocardial matrix metalloproteinase activity in a rat model of heart failure Cardiovasc Res, February 15, 2006; 69(3): 726 - 735. [Abstract] [Full Text] [PDF]
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J.-O Deguchi, E. Aikawa, P. Libby, J. R. Vachon, M. Inada, S. M. Krane, P. Whittaker, and M. Aikawa Matrix Metalloproteinase-13/Collagenase-3 Deletion Promotes Collagen Accumulation and Organization in Mouse Atherosclerotic Plaques Circulation, October 25, 2005; 112(17): 2708 - 2715. [Abstract] [Full Text] [PDF]
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 K. M. Parmar, V. Nambudiri, G. Dai, H. B. Larman, M. A. Gimbrone Jr., and G. Garcia-Cardena Statins Exert Endothelial Atheroprotective Effects via the KLF2 Transcription Factor J. Biol. Chem., July 22, 2005; 280(29): 26714 - 26719. [Abstract] [Full Text] [PDF]
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R. Corti, V. Fuster, Z. A. Fayad, S. G. Worthley, G. Helft, W. F. Chaplin, J. Muntwyler, J. F. Viles-Gonzalez, J. Weinberger, D. A. Smith, et al. Effects of Aggressive Versus Conventional Lipid-Lowering Therapy by Simvastatin on Human Atherosclerotic Lesions: A Prospective, Randomized, Double-Blind Trial With High-Resolution Magnetic Resonance Imaging J. Am. Coll. Cardiol., July 5, 2005; 46(1): 106 - 112. [Abstract] [Full Text] [PDF]
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M. Kawasaki, K. Sano, M. Okubo, H. Yokoyama, Y. Ito, I. Murata, K. Tsuchiya, S. Minatoguchi, X. Zhou, H. Fujita, et al. Volumetric Quantitative Analysis of Tissue Characteristics of Coronary Plaques After Statin Therapy Using Three-Dimensional Integrated Backscatter Intravascular Ultrasound J. Am. Coll. Cardiol., June 21, 2005; 45(12): 1946 - 1953. [Abstract] [Full Text] [PDF]
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H. Lorenz, C. Junger, K. Seidl, A. Gitt, S. Schneider, R. Schiele, H. Wienbergen, R. Winkler, M. Gottwik, W. Delius, et al. Do statins influence the prognostic impact of non-sustained ventricular tachycardia after ST-elevation myocardial infarction? Eur. Heart J., June 1, 2005; 26(11): 1078 - 1085. [Abstract] [Full Text] [PDF]
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P. Stawowy, H. Meyborg, D. Stibenz, N. B. P. Stawowy, M. Roser, U. Thanabalasingam, J. P. Veinot, M. Chretien, N. G. Seidah, E. Fleck, et al. Furin-Like Proprotein Convertases Are Central Regulators of the Membrane Type Matrix Metalloproteinase-Pro-Matrix Metalloproteinase-2 Proteolytic Cascade in Atherosclerosis Circulation, May 31, 2005; 111(21): 2820 - 2827. [Abstract] [Full Text] [PDF]
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T. Senokuchi, T. Matsumura, M. Sakai, M. Yano, T. Taguchi, T. Matsuo, K. Sonoda, D. Kukidome, K. Imoto, T. Nishikawa, et al. Statins Suppress Oxidized Low Density Lipoprotein-induced Macrophage Proliferation by Inactivation of the Small G Protein-p38 MAPK Pathway J. Biol. Chem., February 25, 2005; 280(8): 6627 - 6633. [Abstract] [Full Text] [PDF]
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A. Undas, K. E. Brummel-Ziedins, and K. G. Mann Statins and Blood Coagulation Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 287 - 294. [Abstract] [Full Text] [PDF]
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 A. C. Newby Dual Role of Matrix Metalloproteinases (Matrixins) in Intimal Thickening and Atherosclerotic Plaque Rupture Physiol Rev, January 1, 2005; 85(1): 1 - 31. [Abstract] [Full Text] [PDF]
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 S. K. Mandal, A. Iakhiaev, U. R. Pendurthi, and L. V. M. Rao Acute cholesterol depletion impairs functional expression of tissue factor in fibroblasts: modulation of tissue factor activity by membrane cholesterol Blood, January 1, 2005; 105(1): 153 - 160. [Abstract] [Full Text] [PDF]
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 S Van Doornum, G McColl, and I P Wicks Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis Ann Rheum Dis, December 1, 2004; 63(12): 1571 - 1575. [Abstract] [Full Text] [PDF]
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Y. Fukumoto, J.-o Deguchi, P. Libby, E. Rabkin-Aikawa, Y. Sakata, M. T. Chin, C. C. Hill, P. R. Lawler, N. Varo, F. J. Schoen, et al. Genetically Determined Resistance to Collagenase Action Augments Interstitial Collagen Accumulation in Atherosclerotic Plaques Circulation, October 5, 2004; 110(14): 1953 - 1959. [Abstract] [Full Text] [PDF]
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E. Trogan, Z. A. Fayad, V. V. Itskovich, J.-G. S. Aguinaldo, V. Mani, J. T. Fallon, I. Chereshnev, and E. A. Fisher Serial Studies of Mouse Atherosclerosis by In Vivo Magnetic Resonance Imaging Detect Lesion Regression After Correction of Dyslipidemia Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1714 - 1719. [Abstract] [Full Text] [PDF]
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 J. Li, S.-P. Zhao, D.-q. Peng, Z.-m. Xu, and H.-n. Zhou Early Effect of Pravastatin on Serum Soluble CD40L, Matrix Metalloproteinase-9, and C-Reactive Protein in Patients with Acute Myocardial Infarction Clin. Chem., September 1, 2004; 50(9): 1696 - 1699. [Full Text] [PDF]
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S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]
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U. Schonbeck and P. Libby Inflammation, Immunity, and HMG-CoA Reductase Inhibitors: Statins as Antiinflammatory Agents? Circulation, June 1, 2004; 109(21_suppl_1): II-18 - II-26. [Abstract] [Full Text] [PDF]
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Z. Xu, S. Zhao, H. Zhou, H. Ye, and J. Li Atorvastatin Lowers Plasma Matrix Metalloproteinase-9 in Patients with Acute Coronary Syndrome Clin. Chem., April 1, 2004; 50(4): 750 - 753. [Full Text] [PDF]
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 N. R. Veillard, B. Kwak, G. Pelli, F. Mulhaupt, R. W. James, A. E.I. Proudfoot, and F. Mach Antagonism of RANTES Receptors Reduces Atherosclerotic Plaque Formation in Mice Circ. Res., February 6, 2004; 94(2): 253 - 261. [Abstract] [Full Text] [PDF]
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M. Pynn, K. Schafer, S. Konstantinides, and M. Halle Exercise Training Reduces Neointimal Growth and Stabilizes Vascular Lesions Developing After Injury in Apolipoprotein E-Deficient Mice Circulation, January 27, 2004; 109(3): 386 - 392. [Abstract] [Full Text] [PDF]
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 J. P. Werba, E. Tremoli, P. Massironi, M. Camera, A. Cannata, F. Alamanni, P. Biglioli, and A. Parolari Statins in coronary bypass surgery: rationale and clinical use Ann. Thorac. Surg., December 1, 2003; 76(6): 2132 - 2140. [Abstract] [Full Text] [PDF]
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K. Shimizu, M. Aikawa, K. Takayama, P. Libby, and R. N. Mitchell Direct Anti-Inflammatory Mechanisms Contribute to Attenuation of Experimental Allograft Arteriosclerosis by Statins Circulation, October 28, 2003; 108(17): 2113 - 2120. [Abstract] [Full Text] [PDF]
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E. Jeanpierre, T. Le Tourneau, I. Six, C. Zawadzki;, E. Van Belle, M. D. Ezekowitz, R. Bordet, S. Susen, B. Jude, and D. Corseaux Dietary Lipid Lowering Modifies Plaque Phenotype in Rabbit Atheroma After Angioplasty: A Potential Role of Tissue Factor Circulation, October 7, 2003; 108(14): 1740 - 1745. [Abstract] [Full Text] [PDF]
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R.P. Brandes, S. Beer, T. Ha, and R. Busse Withdrawal of Cerivastatin Induces Monocyte Chemoattractant Protein 1 and Tissue Factor Expression in Cultured Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1794 - 1800. [Abstract] [Full Text] [PDF]
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S. Kinlay, G. G. Schwartz, A. G. Olsson, N. Rifai, S. J. Leslie, W. J. Sasiela, M. Szarek, P. Libby, P. Ganz, and for the Myocardial Ischemia Reduction with Aggress High-Dose Atorvastatin Enhances the Decline in Inflammatory Markers in Patients With Acute Coronary Syndromes in the MIRACL Study Circulation, September 30, 2003; 108(13): 1560 - 1566. [Abstract] [Full Text] [PDF]
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K. Node, M. Fujita, M. Kitakaze, M. Hori, and J. K. Liao Short-Term Statin Therapy Improves Cardiac Function and Symptoms in Patients With Idiopathic Dilated Cardiomyopathy Circulation, August 19, 2003; 108(7): 839 - 843. [Abstract] [Full Text] [PDF]
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 S S Pierangeli and E N Harris Probing antiphospholipid-mediated thrombosis: the interplay between anticardiolipin antibodies and endothelial cells Lupus, July 1, 2003; 12(7): 539 - 545. [Abstract] [PDF]
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Z. Luan, A. J. Chase, and A. C. Newby Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 769 - 775. [Abstract] [Full Text] [PDF]
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J. Genest and T. R. Pedersen Prevention of Cardiovascular Ischemic Events: High-Risk and Secondary Prevention Circulation, April 22, 2003; 107(15): 2059 - 2065. [Full Text] [PDF]
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K. Masamura, K. Oida, H. Kanehara, J. Suzuki, S. Horie, H. Ishii, and I. Miyamori Pitavastatin-Induced Thrombomodulin Expression by Endothelial Cells Acts Via Inhibition of Small G Proteins of the Rho Family Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 512 - 517. [Abstract] [Full Text] [PDF]
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P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]
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P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
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K. Morishige, H. Shimokawa, Y. Matsumoto, Y. Eto, T. Uwatoku, K. Abe, K. Sueishi, and A. Takeshita Overexpression of matrix metalloproteinase-9 promotes intravascular thrombus formation in porcine coronary arteries in vivo Cardiovasc Res, February 1, 2003; 57(2): 572 - 585. [Abstract] [Full Text] [PDF]
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 F. J. Schoen and R. F. Padera Jr. Cardiac Surgical Pathology Card. Surg. Adult, January 1, 2003; 2(2003): 119 - 185. [Full Text]
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R. Corti, V. Fuster, Z. A. Fayad, S. G. Worthley, G. Helft, D. Smith, J. Weinberger, J. Wentzel, G. Mizsei, M. Mercuri, et al. Lipid Lowering by Simvastatin Induces Regression of Human Atherosclerotic Lesions: Two Years' Follow-Up by High-Resolution Noninvasive Magnetic Resonance Imaging Circulation, December 3, 2002; 106(23): 2884 - 2887. [Abstract] [Full Text] [PDF]
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P. Di Napoli, A.A. Taccardi, M. Oliver, and R. De Caterina Statins and stroke: evidence for cholesterol-independent effects Eur. Heart J., December 2, 2002; 23(24): 1908 - 1921. [PDF]
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L. G. Bucciarelli, T. Wendt, W. Qu, Y. Lu, E. Lalla, L. L. Rong, M. T. Goova, B. Moser, T. Kislinger, D. C. Lee, et al. RAGE Blockade Stabilizes Established Atherosclerosis in Diabetic Apolipoprotein E-Null Mice Circulation, November 26, 2002; 106(22): 2827 - 2835. [Abstract] [Full Text] [PDF]
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W. Palinski and C. Napoli Unraveling Pleiotropic Effects of Statins on Plaque Rupture Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1745 - 1750. [Full Text] [PDF]
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 C. Kluft, R. Kleemann, and M.P.M. de Maat How best to counteract the enemies? By controlling inflammation in the coronary circulation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G53 - G65. [Abstract] [PDF]
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A. C. Sposito and M. J. Chapman Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1524 - 1534. [Abstract] [Full Text] [PDF]
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M. Aikawa, S. Sugiyama, C. C. Hill, S. J. Voglic, E. Rabkin, Y. Fukumoto, F. J. Schoen, J. L. Witztum, and P. Libby Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma Circulation, September 10, 2002; 106(11): 1390 - 1396. [Abstract] [Full Text] [PDF]
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K. K. Koh, J. W. Son, J. Y. Ahn, D. K. Jin, H. S. Kim, Y. M. Choi, D. S. Kim, E.-M. Jeong, G. S. Park, I. S. Choi, et al. Comparative Effects of Diet and Statin on NO Bioactivity and Matrix Metalloproteinases in Hypercholesterolemic Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): e19 - 23. [Abstract] [Full Text] [PDF]
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G. K. Sukhova, J. K. Williams, and P. Libby Statins Reduce Inflammation in Atheroma of Nonhuman Primates Independent of Effects on Serum Cholesterol Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1452 - 1458. [Abstract] [Full Text] [PDF]
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P. Schoenhagen, E. M. Tuzcu, and S. G. Ellis Plaque Vulnerability, Plaque Rupture, and Acute Coronary Syndromes: (Multi)-Focal Manifestation of a Systemic Disease Process Circulation, August 13, 2002; 106(7): 760 - 762. [Full Text] [PDF]
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L. K. Newby, A. Kristinsson, M. V. Bhapkar, P. E. Aylward, A. P. Dimas, W. W. Klein, D. K. McGuire, D. J. Moliterno, F. W. A. Verheugt, W. D. Weaver, et al. Early Statin Initiation and Outcomes in Patients With Acute Coronary Syndromes JAMA, June 19, 2002; 287(23): 3087 - 3095. [Abstract] [Full Text] [PDF]
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R. Baetta, M. Camera, C. Comparato, C. Altana, M. D. Ezekowitz, and E. Tremoli Fluvastatin Reduces Tissue Factor Expression and Macrophage Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the Absence of Lipid Lowering Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 692 - 698. [Abstract] [Full Text] [PDF]
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P. Libby and M. Aikawa Vitamin C, Collagen, and Cracks in the Plaque Circulation, March 26, 2002; 105(12): 1396 - 1398. [Full Text] [PDF]
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K. E. Ferrier, M. H. Muhlmann, J.-P. Baguet, J. D. Cameron, G. L. Jennings, A. M. Dart, and B. A. Kingwell Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension J. Am. Coll. Cardiol., March 20, 2002; 39(6): 1020 - 1025. [Abstract] [Full Text] [PDF]
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P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
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S. H. Wilson, J. Herrmann, L. O. Lerman, D. R. Holmes Jr, C. Napoli, E. L. Ritman, and A. Lerman Simvastatin Preserves the Structure of Coronary Adventitial Vasa Vasorum in Experimental Hypercholesterolemia Independent of Lipid Lowering Circulation, January 29, 2002; 105(4): 415 - 418. [Abstract] [Full Text] [PDF]
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H. V. Anderson, J. McNatt, F. J. Clubb, M. Herman, J.-P. Maffrand, F. DeClerck, C. Ahn, L. M. Buja, and J. T. Willerson Platelet Inhibition Reduces Cyclic Flow Variations and Neointimal Proliferation in Normal and Hypercholesterolemic-Atherosclerotic Canine Coronary Arteries Circulation, November 6, 2001; 104(19): 2331 - 2337. [Abstract] [Full Text] [PDF]
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M. Takemoto and J. K. Liao Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1712 - 1719. [Abstract] [Full Text] [PDF]
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 A. Farzaneh-Far, J. Rudd, and P. L Weissberg Inflammatory mechanisms: Ischaemic heart disease Br. Med. Bull., October 1, 2001; 59(1): 55 - 68. [Abstract] [Full Text] [PDF]
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P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF]
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M. A. Albert, E. Danielson, N. Rifai, P. M Ridker, and for the PRINCE Investigators Effect of Statin Therapy on C-Reactive Protein Levels: The Pravastatin Inflammation/CRP Evaluation (PRINCE): A Randomized Trial and Cohort Study JAMA, July 4, 2001; 286(1): 64 - 70. [Abstract] [Full Text] [PDF]
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M. Aikawa and P. Libby Vascular inflammation and activation: new targets for lipid lowering Eur. Heart J. Suppl., May 1, 2001; 3(suppl_B): B3 - B11. [Abstract] [PDF]
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P. M. Ridker, N. Rifai, and S. P. Lowenthal Rapid Reduction in C-Reactive Protein With Cerivastatin Among 785 Patients With Primary Hypercholesterolemia Circulation, March 6, 2001; 103(9): 1191 - 1193. [Abstract] [Full Text] [PDF]
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Y. Fukumoto, P. Libby, E. Rabkin, C. C. Hill, M. Enomoto, Y. Hirouchi, M. Shiomi, and M. Aikawa Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits Circulation, February 20, 2001; 103(7): 993 - 999. [Abstract] [Full Text] [PDF]
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R. Baetta, M. Camera, C. Comparato, C. Altana, M. D. Ezekowitz, and E. Tremoli Fluvastatin Reduces Tissue Factor Expression and Macrophage Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the Absence of Lipid Lowering Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 692 - 698. [Abstract] [Full Text] [PDF]
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M. Eto, T. Kozai, F. Cosentino, H. Joch, and T. F. Luscher Statin Prevents Tissue Factor Expression in Human Endothelial Cells: Role of Rho/Rho-Kinase and Akt Pathways Circulation, April 16, 2002; 105(15): 1756 - 1759. [Abstract] [Full Text] [PDF]
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