© 1995 American Heart Association, Inc.
Articles |
Rapamycin-FKBP Inhibits Cell Cycle Regulators of Proliferation in Vascular Smooth Muscle Cells
From the Cardiovascular Institute, Molecular Medicine Program, Department of Medicine, and Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, NY.
Correspondence to Andrew R. Marks, Box 1269, Mount Sinai School of Medicine, One Gustave L. Levy Pl, New York, NY 10029.
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Abstract |
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Abstract Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosuppressant and a potent inhibitor of cellular proliferation. In the present study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effects of a related immunosuppressant, FK520. In vascular smooth muscle cells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA synthesis and cell growth. FK520, an analogue of the immunosuppressant FK506, is structurally related to rapamycin and binds to FKBP but did not inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that the effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhibited retinoblastoma protein phosphorylation at the G1/S transition. This inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33cdk2 kinase activity. These observations suggest that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.
Key Words: immunophilin • accelerated arteriosclerosis • antiproliferation • transplantation • FK506
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Introduction |
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Abnormal vascular smooth muscle cell (VSMC) proliferation is involved in restenosis following percutaneous transluminal angioplasty (PTCA) and accelerated arteriosclerosis after cardiac transplantation.1 2 3 Restenosis occurs after
30% to 40% of the procedures,1 4 limiting the utility
of PTCA. Accelerated arteriosclerosis in coronary arteries of the donor
heart is a major factor limiting long-term survival of cardiac
transplant recipients.3 5 6 Common to both pathological
processes is an injury to the vascular endothelial cell barrier
resulting in activation of VSMC proliferation. Multiple signaling
pathways can trigger a proliferative response in VSMC. The complexity
of cell growth signaling has made it difficult to achieve adequate
control of VSMC proliferation in patients. Much attention has focused on understanding the mechanisms underlying the proliferative response in VSMC. It has been proposed that identifying the regulators of this proliferative response in VSMC may lead to therapeutic strategies aimed at blocking or inhibiting VSMC growth. After deendothelialization of arteries by mechanical injury during PTCA, or by an immune mechanism in transplant recipients, VSMC leave their quiescent state (G0/G1) and enter the cell cycle. Recent studies have shown that early response genes including c-fos and c-myc are induced after exit from G0.7 8 Cell-cycle kinases including p34cdc2 and mitogen-activated protein kinase homologues appear to be involved in signaling VSMC growth, leading to induction of early response genes.9 On the other hand, transforming growth factor-ß1 inhibits smooth muscle cells causing a G1 arrest10 11 that is associated with a decrease in p34cdc2 kinase activity.12 These and other similar observations have led a number of investigators to focus on cell-cycle regulators as potential therapeutic targets for inhibiting VSMC proliferation. For example, antisense oligonucleotides to c-myc, c-myb, c-fos, cyclin A, p34cdc2 kinase, and proliferating cell nuclear antigen have been used with varying degrees of success to inhibit VSMC proliferation.11 13 14
Recent studies in a rat heart transplantation model have suggested that the macrolide antibiotic FK506, currently used as an immunosuppressant after some types of organ transplant, may accelerate transplant coronary arteriosclerosis.15 16 17 In animal models, rapamycin, also a macrolide antibiotic, appears to retard the development of accelerated arteriosclerosis after allograft transplantation and restenosis following mechanical injury.15 18 19 20
In the present study, we sought to compare the effects of rapamycin and FK520 on VSMC proliferation. We found that rapamycin, but not FK520, inhibits cell growth in both human and rat VSMC. This inhibition of cell growth by rapamycin was associated with decreases in cell-cycle kinase activity at the G1/S and G2/M transitions. Phosphorylation of retinoblastoma protein (pRb), a marker for cell-cycle progression, was also reduced. Our data suggest that inhibition of cell-cycle kinases by rapamycin contributes to its potent antiproliferative effects in VSMC. Moreover, because the mechanism of the antiproliferative effect of rapamycin involves inhibition of cell-cycle kinases, rapamycin should block VSMC growth regardless of the stimulus that initiates the VSMC proliferative response. FK520, an analogue of FK506, nonsignificantly accelerated VSMC growth and increased the activity of the cell-cycle regulators. Thus, compared with FK520, rapamycin has antiproliferative properties that might make it a better choice for use in cardiac transplant recipients in whom VSMC proliferation is a potentially serious problem.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Reagents
Rapamycin was a gift from Wyeth-Ayerst Research Laboratory (Dr Suren Sehgal), and FK520 (an FK506 analogue) was provided by Dr John Siekierka (Merck). [3H]Thymidine was from NEN, and polyclonal anti-p34cdc2 kinase antibody was a gift from Dr Hiroaki Kiyokawa (Memorial Sloan-Kettering Cancer Institute). Polyclonal antibodies to cyclin D (raised against the C-terminal domain of human cyclin D) and cdk2 (raised against a synthetic peptide in the C-terminal domain of human cdk2) were from Upstate Biotechnology Inc. pRb antibody was from Pharmingen.
Cell Culture
Rat aortic smooth muscle cells (RASM, isolation No.
1120)21 22 23 and human aortic smooth muscle cells were gifts
from Dr Mark Taubman (Mount Sinai School of Medicine). RASM (passages 8
to 11) were cultured in Dulbecco's modified essential medium (DMEM)
plus 20% fetal calf serum (FCS, GIBCO), 100 U/mL penicillin, and 100
µg/mL streptomycin as previously described.21 Medium was
changed every 48 hours. When cultured in 20% FCS, RASM double
approximately every 16 to 20 hours. Human aortic smooth muscle cells
from ascending aorta obtained from the donor at the time of cardiac
transplantation were cultured in DMEM plus 20% FCS. After plating,
rapamycin (100 ng/mL) and FK520 (100 ng/mL) were added directly to
DMEM. Cell proliferation analyses were performed by counting triplicate
plates at the indicated times during a 7-day period by using a Coulter
counter. Cell viability was determined with trypan blue stain for each
experiment. Results represent the mean values from three
separate experiments; error bars represent the standard error
of the mean.
DNA Synthesis
For determination of DNA synthesis, [3H]thymidine
incorporation was measured, and microcultures of 5000 cells were
established in quadruplicates in flat-bottom 96-well microtiter plates
in the presence and absence of varying concentrations of drugs. After
48 hours, each culture was pulsed with 1 µCi
[3H]thymidine and harvested 16 to 20 hours later by using
a Cambridge Technology PHD Harvester. [3H]Thymidine
incorporation was measured in a liquid scintillation counter. The
competition experiment with FK520 was performed with 2 ng/mL rapamycin
and concentrations of FK520 between 2 and 500 ng/mL.
Flow Cytometric Analysis
Cells were treated with either 100 ng/mL rapamycin or FK520 for
24 hours, harvested, and washed in ice-cold phosphate-buffered saline
(PBS), fixed in 70% ethanol, and stored overnight at 4°C before
analysis. Cells were then washed once with ice-cold PBS treated
with RNAse (1 hour at 37°C, 500 U/mL). Cellular DNA was stained with
propidium iodide (50 µg/mL). Cell-cycle determination was performed
by using a Coulter analyzer. Results represent a minimum of
3000 cells assayed for each determination.
Preparation of Cellular Lysates
RASM growing in log phase were plated at 30% confluence.
After 24 hours in DMEM+20% FCS, plates were washed twice with PBS and
transferred to DMEM+0.5% FCS for 72 hours to achieve quiescence.
Plates were then stimulated with 20% FCS and treated with either no
drugs (control), 100 ng/mL rapamycin, or 100 ng/mL FK520. After the
indicated time period, plates were washed twice with ice-cold PBS, and
cell lysates were prepared using Rb lysis buffer (50 mmol/L Tris-HCl,
pH 8.0, 120 mmol/L NaCl, 1 mmol/L EDTA, 0.1 mmol/L NaF, 0.2 mmol/L
Na3VO4, 10 mmol/L ß-glycerophosphate,
1 mmol/L dithiothreitol, 0.5 mmol/L phenylmethylsulfonyl fluoride, 1
µg/mL aprotinin, 1 µg/mL leupeptin, 10 µg/mL soybean trypsin
inhibitor, and 0.5% Nonidet P-40). Cells were scraped off the bottom
of the plates, and lysates were rocked for 1 hour at 4°C. Lysates
were stored at -70°C. Protein concentration was measured by using
the Bradford reagent (Bio-Rad), with bovine serum albumin used as a
standard.
Determination of Cyclin-Dependent Kinase Activities
Activities of p34cdc2 and
p33cdk2 kinases were analyzed essentially as
described previously,24 with some modifications. Protein
extracts (100 µg) were diluted to 500 µL with RIPA buffer (50
mmol/L Tris-HCl, pH 7.4, 250 mmol/L NaCl, 5 mmol/L EDTA, 50 mmol/L NaF,
0.1 mmol/L Na3VO4, 0.5 mmol/L
phenylmethylsulfonyl fluoride, 1 µg/mL aprotinin, 1 µg/mL
leupeptin, 1% Nonidet P-40, 0.5% sodium deoxycholate, and 0.1%
sodium dodecyl sulfate [SDS]). RASM lysates were immunoprecipitated
with either anti-p34cdc2 kinase
C-terminus–specific antiserum25 or a human polyclonal
anti-p33cdk2 kinase antibody. Protein
A–Sepharose beads (20 µL) were added and gently rocked for 1 hour at
4°C. Samples were centrifuged and washed twice with RIPA buffer,
twice with RIPA without NaCl, and twice with kinase assay buffer
(mmol/L: Tris-HCl 50, pH 7.4, MgCl2 10, and dithiothreitol
1). Phosphorylation was carried out in 25 µL of kinase buffer with
the addition of 0.1 mg/mL of histone H1 (Boehringer Mannheim) and 50
µCi [
-32P]ATP for 15 minutes at 28°C. The reaction
was terminated with the addition of 6 µL of 6x Laemmli's sample
loading buffer and boiled for 5 minutes. Samples (15 µL) were
analyzed on a 12% SDS-polyacrylamide gel. Gels were dried for 2 hours
and analyzed by using [-32P]ATP standards and a
phosphorimager.
Measurement of Retinoblastoma Protein Levels
Protein extracts (50 µg) were size-fractionated on 7.5% gels
and transferred to nitrocellulose overnight at 60 V. Filters were
blocked in PBS containing 0.1% Tween-20 (PBS-T) and 5% dry milk for 1
hour at 30°C, followed by incubation overnight with anti-pRb antibody
(1/1000 dilution) at 4°C. The filters were washed with PBS-T, then
incubated with the secondary antibody conjugated to peroxidase (goat
anti-mouse IgG) for 1 hour at 4°C, and washed; signals were detected
by using the chemiluminescence detection system (ECL) followed by
exposure to Kodak XAR film. Autoradiographic signals were quantified by
scanning the gels by use of a Macintosh computer with ADOBE
PHOTOSHOP and IMAGE 1.44 software. The ratio of
hyperphosphorylated to hypophosphorylated pRb was calculated for each
time point and plotted. Results are shown for a representative
experiment. This experiment was repeated three times, and similar
results were obtained each time.
Measurement of Cyclin-Dependent Kinase and Cyclin Protein
Levels
Protein extracts (50 µg) were electrophoresed on separate 12%
SDS-polyacrylamide gels and transferred to nitrocellulose overnight at
45 V. Filters were blocked in PBS containing 0.1% Tween 20 and 5% dry
milk for 1 hour at room temperature, followed by incubation overnight
with anti-p34cdc2 antibody (1/1000 dilution),
anti-p33cdk2 antibody (2.5 µg/mL), or
anti–cyclin D antibody (2.5 mg/mL). The filters were then washed,
incubated with goat anti-rabbit IgG conjugated to peroxidase for 1 hour
at 4°C, and washed again; signals were detected by using the
chemiluminescence detection system (Bio-Rad) and exposed to Kodak XAR
films. Results are shown for representative experiments. These
experiments were repeated three times, and similar results were
obtained each time.
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Results |
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Rapamycin as low as 1 ng/mL, but not FK520 at any dose tested, inhibited RASM proliferation (P<.05, Fig 1
).
Rapamycin also decreased [3H]thymidine incorporation in a
dose-dependent manner (P<.01, Fig 2A). The
inhibition of proliferation produced by rapamycin persisted at least
through 7 days (168 hours) of cell culture. Similarly, rapamycin
inhibited human aortic smooth muscle cell proliferation by 50% after
72 hours (P<.05; Fig 1, inset). In contrast, FK520
increased cell growth compared with control, but the differences were
not significant. Cell viability, as assessed by trypan blue staining,
was >99% in control, rapamycin-treated, and FK520-treated cells. The
effect of rapamycin in terms of inhibiting DNA synthesis was competed
by a molar excess of FK520 (Fig 2B). This result indicates that the
reduction in [3H]thymidine incorporation was probably
mediated by rapamycin binding to the immunophilin FKBP, since both
rapamycin and FK520 share this same cytosolic receptor. FK520 at low
concentrations (eg, 2.5 ng/mL) caused a small but significant
(P<.05) decrease in DNA synthesis (Fig 2A), and there was a
small additive effect of FK520 (only at low concentrations, eg, 8 and
16 ng/mL) combined with rapamycin in terms of decreasing DNA synthesis
(Fig 2B).
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Rapamycin, but not FK520, delayed progression from G1 to S as assessed
by cell-cycle analysis using propidium iodide staining. After
stimulation with 20% FCS, 30% of cells progressed from G1/S and
G2/M. The effect of rapamycin was to reduce progression from G1/S and
G2/M to 10% of cells. pRb phosphorylation is believed to be a
marker for progression from G1 to S. Hypophosphorylated pRb suppresses
the progression from G1 to S,26 and hyperphosphorylation
generally occurs 1 to 2 hours before the G1/S
transition.27 28 Cells in early G1 contain exclusively
hypophosphorylated pRb. At an undefined point in late G1, pRb is
hyperphosphorylated and remains hyperphosphorylated until M. In
quiescent RASM (maintained in 0.5% FCS for 72 hours), pRb
phosphorylation occurred 6 to 8 hours after stimulation with 20% FCS.
Culturing cells with rapamycin (100 ng/mL) delayed the onset of pRb
hyperphosphorylation in RASM by 6 hours to 12 hours after G0 and
reduced the levels of phosphorylation at each time point sampled (Fig 3). In contrast, FK520 nonsignificantly accelerated the
time course of pRb phosphorylation (Fig 3).
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Progression through the cell cycle is dependent on the activity of
specific cell-cycle kinases, several of which, including cdk2 and cdk4,
are thought to phosphorylate pRb. We examined the effects of rapamycin
and FK520 on the activity of several cell-cycle kinases in VSMC. In
RASM compared with control cells, p34cdc2 kinase
activity was decreased 16 to 20 hours after G0 by rapamycin but not
by FK520 (Fig 4A). Protein levels of
p34cdc2 kinase were unchanged throughout the
cell cycle (Fig 4A, insets). The decrease in
p34cdc2 kinase activity at 16 to 20 hours
corresponds to the G2/M transition in RASM. At earlier time points
(during the G1/S transition), p34cdc2 kinase
activity was low despite steady levels of
p34cdc2 protein, suggesting that it may have
little effect at this point in the cell cycle in RASM (Fig 4A).
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Compared with control cells, rapamycin (100 ng/mL) decreased
p33cdk2 kinase activity beginning at 10 hours
through 16 hours after G0 (Fig 4B
). The period from 10 to 16 hours
after G0 corresponds to the time during which pRb phosphorylation is
decreased by rapamycin-FKBP (Fig 3). Protein levels for
p33cdk2 kinase were unchanged throughout the
cell cycle compared with control cells (Fig 4B, insets), indicating
that the decrease in p33cdk2 kinase activity was
not due to a decrease in p33cdk2 synthesis.
These data suggest that the inhibition of pRb phosphorylation could at
least in part be due to a decrease in p33cdk2
kinase activity.
A regulatory role for cyclin D1 has been proposed with regard to pRb
phosphorylation.29 30 Interactions between cyclin D1 and a
variety of cyclin-dependent kinases have been reported, and the
expression of D-type cyclins is regulated by growth
factors.31 We sought to determine, on the basis of these
observations, whether the antiproliferative effects of rapamycin in
RASM were associated with regulation of cyclin D1. Cyclin D1 levels
were elevated in control RASM at 10 hours after G0, corresponding to
the onset of pRb phosphorylation. Rapamycin delayed the onset of this
rise in cyclin D1 levels by 4 to 6 hours (data not shown). The
reduction in cyclin D1 levels by rapamycin occurred at the point when
pRb phosphorylation was reduced.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data show that the antiproliferative effects of rapamycin in VSMC are associated with an inhibition of cell-cycle kinases, cyclins, and pRb phosphorylation. These data imply that phosphorylation of pRb plays an important role in signaling during smooth muscle proliferation. In contrast, FK520, another potentially useful drug for immunosuppression following cardiac transplantation, induces a nonsignificant increase in VSMC proliferation associated with an acceleration of the time course and extent of pRb phosphorylation (Figs 1
and 3). The antiproliferative effects of rapamycin appear to be
mediated by binding to the cytosolic receptor FKBP because they are
competed by FK520, a drug that shares the same receptor. However, these
studies do not exclude the possibility that these drugs also interact
with other binding sites in RASM.
We observed small but significant effects only at low
concentrations of FK520 (2 to 20 ng/mL) in terms of inhibiting DNA
synthesis. However, the physiological importance of these effects was
questionable because we never observed any inhibition of RASM
proliferation when using either FK520 or FK506 at any concentration.
Indeed, to the contrary, we have consistently observed a small
nonsignificant increase in proliferation when using either FK520 or
FK506. Moreover, FK520 increases pRb phosphorylation and cell-cycle
kinase activity (Figs 3 and 4), suggesting that it accelerates
cell-cycle progression.
Cyclin-dependent kinases, including cdk2, have been implicated as regulators of pRb function.32 33 34 Although the data suggest that a cyclin-dependent kinase phosphorylates pRb in vitro, there remains some controversy as to which kinase and how many actually carry out this function in vivo. We found that rapamycin but not FK520 decreased the activity of p33cdk2 kinase35 in VSMC. This finding does not indicate that pRb phosphorylation is dependent on p33cdk2 kinase but suggests that this kinase could be involved in regulating pRb function in VSMC. We did not examine the activities of other kinases that similarly could be playing a role in phosphorylating pRb. Indeed, determining the specific kinase(s) that phosphorylates pRb would be interesting but is not required to support the main point of the present study, which is that the antiproliferative effects of rapamycin in VSMC are associated with inhibition of regulators of cell-cycle progression. Similarly, the finding that rapamycin decreased the activity of cell-cycle kinases and the levels of a cyclin (D1) does not rule out the possibility that rapamycin could have effects on other regulators of cell growth as well.
p34cdc2 kinase is thought to play an important regulatory role in the G2/M transition.36 37 The time course for inhibition of p34cdc2 kinase activity by rapamycin suggests that this kinase may play an important role in the G2/M transition in VSMC. In another myogenic cell line, BC3H1 cells, we had previously shown that rapamycin inhibited proliferation and induced differentiation and that these effects were also associated with a reduction in p34cdc2 kinase activity.24 However, in BC3H1 cells, the decrease in p34cdc2 kinase activity occurs at the G1/S transition. The p34cdc2 kinase may have multiple roles in the cell cycle, depending on which cell type is examined.
The growth-inhibitory effects of rapamycin (Fig 1) in VSMC are long
lasting. In contrast, inhibition of pRb phosphorylation (Fig 3) and
cell-cycle kinase activity (Fig 4) appears to be more of a transient
delay rather than a complete block. Moreover, examination of the cell
growth data in Fig 1 shows that although growth is significantly
suppressed by rapamycin, there is some slow growth in the
rapamycin-treated cells. Indeed, taken together, these data suggest
that rapamycin significantly lengthens the cell cycle by introducing
delays at the G1/S and G2/M transition points. These delays appear to
result in a marked prolongation of the doubling time for the VSMC
exposed to rapamycin (Fig 1). Some of the cell-cycle kinase activity
and phosphorylation of pRb observed later in the cell cycle (eg, at 16
to 20 hours) in the rapamycin-treated cells may reflect the fact that
the cell cultures were not synchronized. Thus, a subset of cells was
past the G1/S transition at the start of the experiment, despite
culturing in low-serum medium for 72 hours to induce quiescence.
It is believed that immunologic events linked to HLA incompatibility between the donor and host may result in vascular injury, leading to VSMC proliferation. Moreover, accelerated arteriosclerosis is not limited to cardiac transplant patients, as other organ allografts are subject to similar processes.38 Cyclosporin A, one of the most widely used immunosuppressants, appears to have a neutral effect on accelerated arteriosclerosis.6 15 38 39 The mechanisms underlying post–cardiac transplant–accelerated arteriosclerosis remain poorly understood.5 15 38 40 Nevertheless, VSMC proliferation is the fundamental pathology. Accelerated arteriosclerosis after cardiac transplantation occurs with similar frequency despite the use of newer immunosuppressant agents, including cyclosporin A and FK506. FK506 is currently being used as a therapeutic agent for the prevention of post–cardiac transplant rejection in humans. Our findings predict that FK506 would either be neutral in terms of VSMC proliferation or could have an adverse effect by accelerating the time course and the extent of posttransplant arteriosclerosis. Conversely, since rapamycin both immunosuppresses and blocks VSMC proliferation, it could be the preferred therapeutic agent to reduce accelerated arteriosclerosis following cardiac transplantation and might even prolong survival in cardiac transplant recipients.
Many studies have attempted to identify the factor or factors contributing to VSMC proliferation following vascular injury, particularly after PTCA.2 9 12 21 22 41 42 43 44 45 46 The fact that rapamycin inhibits cell-cycle dependent kinases and phosphorylation of pRb suggests that its effects on VSMC proliferation would not depend on which of the many agents capable of triggering VSMC proliferation after injury are causative. As such, rapamycin might also be a useful agent for reducing or blocking the component of post-PTCA restenosis that is due to VSMC proliferation.
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Acknowledgments |
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This study was supported by grants from the National Institutes of Health (NS-29814), the New York Heart Association, the Sarah Chait and the Louis B. Mayer Foundations (Dr Marks), and a Sable grant (Dr Marx). Dr Marks is a Bristol Meyers-Squibb Established Investigator of the American Heart Association. Drs Marx and Go are ACC/Merck Fellows. We thank Drs Valentin Fuster and Mark B. Taubman for helpful discussions, Dr Taubman for providing rat and human aortic smooth muscle cells, Dr Suren Sehgal of Wyeth-Ayerst for providing rapamycin, and Dr Hiroaki Kiyokawa (Memorial Sloan-Kettering Cancer Institute) for providing anti-p34cdc2 kinase antibody.
Received September 7, 1994; accepted December 2, 1994.
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J. E. Sousa, M. A. Costa, A. C. Abizaid, B. J. Rensing, A. S. Abizaid, L. F. Tanajura, K. Kozuma, G. Van Langenhove, A. G.M.R. Sousa, R. Falotico, et al. Sustained Suppression of Neointimal Proliferation by Sirolimus-Eluting Stents: One-Year Angiographic and Intravascular Ultrasound Follow-Up Circulation, October 23, 2001; 104(17): 2007 - 2011. [Abstract] [Full Text] [PDF]
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 E Regar, G Sianos, and P W Serruys Stent development and local drug delivery Br. Med. Bull., October 1, 2001; 59(1): 227 - 248. [Abstract] [Full Text] [PDF]
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T. Suzuki, G. Kopia, S.-i. Hayashi, L. R. Bailey, G. Llanos, R. Wilensky, B. D. Klugherz, G. Papandreou, P. Narayan, M. B. Leon, et al. Stent-Based Delivery of Sirolimus Reduces Neointimal Formation in a Porcine Coronary Model Circulation, September 4, 2001; 104(10): 1188 - 1193. [Abstract] [Full Text] [PDF]
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S. O. Marx and A. R. Marks Bench to Bedside: The Development of Rapamycin and Its Application to Stent Restenosis Circulation, August 21, 2001; 104(8): 852 - 855. [Full Text] [PDF]
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R. C. Braun-Dullaeus, M. J. Mann, U. Seay, L. Zhang, H. E. von der Leyen, R. E. Morris, and V. J. Dzau Cell Cycle Protein Expression in Vascular Smooth Muscle Cells In Vitro and In Vivo Is Regulated Through Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin Arterioscler Thromb Vasc Biol, July 1, 2001; 21(7): 1152 - 1158. [Abstract] [Full Text] [PDF]
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M. Boehm and E. G. Nabel Cell Cycle and Cell Migration : New Pieces to the Puzzle Circulation, June 19, 2001; 103(24): 2879 - 2881. [Full Text] [PDF]
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J. Sun, S. O. Marx, H.-J. Chen, M. Poon, A. R. Marks, and L. E. Rabbani Role for p27Kip1 in Vascular Smooth Muscle Cell Migration Circulation, June 19, 2001; 103(24): 2967 - 2972. [Abstract] [Full Text] [PDF]
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 L. Dudkin, M. B. Dilling, P. J. Cheshire, F. C. Harwood, M. Hollingshead, S. G. Arbuck, R. Travis, E. A. Sausville, and P. J. Houghton Biochemical Correlates of mTOR Inhibition by the Rapamycin Ester CCI-779 and Tumor Growth Inhibition Clin. Cancer Res., June 1, 2001; 7(6): 1758 - 1764. [Abstract] [Full Text] [PDF]
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S. Huang, L. N. Liu, H. Hosoi, M. B. Dilling, T. Shikata, and P. J. Houghton p53/p21CIP1 Cooperate in Enforcing Rapamycin-induced G1 Arrest and Determine the Cellular Response to Rapamycin Cancer Res., April 1, 2001; 61(8): 3373 - 3381. [Abstract] [Full Text]
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J. E. Sousa, M. A. Costa, A. Abizaid, A. S. Abizaid, F. Feres, I. M. F. Pinto, A. C. Seixas, R. Staico, L. A. Mattos, A. G. M. R. Sousa, et al. Lack of Neointimal Proliferation After Implantation of Sirolimus-Coated Stents in Human Coronary Arteries : A Quantitative Coronary Angiography and Three-Dimensional Intravascular Ultrasound Study Circulation, January 16, 2001; 103(2): 192 - 195. [Abstract] [Full Text] [PDF]
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C. Duan, M. B. Liimatta, and O. L. Bottum Insulin-like Growth Factor (IGF)-I Regulates IGF-binding Protein-5 Gene Expression through the Phosphatidylinositol 3-Kinase, Protein Kinase B/Akt, and p70 S6 Kinase Signaling Pathway J. Biol. Chem., December 24, 1999; 274(52): 37147 - 37153. [Abstract] [Full Text] [PDF]
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M. Grewe, F. Gansauge, R. M. Schmid, G. Adler, and T. Seufferlein Regulation of Cell Growth and Cyclin D1 Expression by the Constitutively Active FRAP-p70s6K Pathway in Human Pancreatic Cancer Cells Cancer Res., August 1, 1999; 59(15): 3581 - 3587. [Abstract] [Full Text] [PDF]
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J. F. GUMMERT, T. IKONEN, and R. E. MORRIS Newer Immunosuppressive Drugs: A Review J. Am. Soc. Nephrol., June 1, 1999; 10(6): 1366 - 1380. [Abstract] [Full Text]
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R. Gallo, A. Padurean, T. Jayaraman, S. Marx, M. Roque, S. Adelman, J. Chesebro, J. Fallon, V. Fuster, A. Marks, et al. Inhibition of Intimal Thickening After Balloon Angioplasty in Porcine Coronary Arteries by Targeting Regulators of the Cell Cycle Circulation, April 27, 1999; 99(16): 2164 - 2170. [Abstract] [Full Text] [PDF]
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J.-M. Li and G. Brooks Cell cycle regulatory molecules (cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors) and the cardiovascular system; potential targets for therapy? Eur. Heart J., March 2, 1999; 20(6): 406 - 420. [PDF]
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H. Hosoi, M. B. Dilling, T. Shikata, L. N. Liu, L. Shu, R. A. Ashmun, G. S. Germain, R. T. Abraham, and P. J. Houghton Rapamycin Causes Poorly Reversible Inhibition of mTOR and Induces p53-independent Apoptosis in Human Rhabdomyosarcoma Cells Cancer Res., February 1, 1999; 59(4): 886 - 894. [Abstract] [Full Text] [PDF]
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R. C. Braun-Dullaeus, M. J. Mann, and V. J. Dzau Cell Cycle Progression : New Therapeutic Target for Vascular Proliferative Disease Circulation, July 7, 1998; 98(1): 82 - 89. [Abstract] [Full Text] [PDF]
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 T. C. Major and J. A. Keiser Inhibition of Cell Growth: Effects of the Tyrosine Kinase Inhibitor CGP 53716 J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 402 - 410. [Abstract] [Full Text]
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M. Weis and W. von Scheidt Cardiac Allograft Vasculopathy : A Review Circulation, September 16, 1997; 96(6): 2069 - 2077. [Abstract] [Full Text]
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M. O. Boluyt, J.-S. Zheng, A. Younes, X. Long, L. O'Neill, H. Silverman, E. G. Lakatta, and M. T. Crow Rapamycin Inhibits {alpha}1-Adrenergic Receptor–Stimulated Cardiac Myocyte Hypertrophy but Not Activation of Hypertrophy-Associated Genes : Evidence for Involvement of p70 S6 Kinase Circ. Res., August 19, 1997; 81(2): 176 - 186. [Abstract] [Full Text]
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N. L. Zhu, L. Wu, P. X. Liu, E. M. Gordon, W. F. Anderson, V. A. Starnes, and F. L. Hall Downregulation of Cyclin G1 Expression by Retrovirus-Mediated Antisense Gene Transfer Inhibits Vascular Smooth Muscle Cell Proliferation and Neointima Formation Circulation, July 15, 1997; 96(2): 628 - 635. [Abstract] [Full Text]
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D. J. Withers, T. Seufferlein, D. Mann, B. Garcia, N. Jones, and E. Rozengurt Rapamycin Dissociates p70S6K Activation from DNA Synthesis Stimulated by Bombesin and Insulin in Swiss 3T3 Cells J. Biol. Chem., January 24, 1997; 272(4): 2509 - 2514. [Abstract] [Full Text] [PDF]
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M. Higaki, H. Sakaue, W. Ogawa, M. Kasuga, and K. Shimokado Phosphatidylinositol 3-Kinase-independent Signal Transduction Pathway for Platelet-derived Growth Factor-induced Chemotaxis J. Biol. Chem., November 15, 1996; 271(46): 29342 - 29346. [Abstract] [Full Text] [PDF]
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H. Koyama, Y. Nishizawa, M. Hosoi, S. Fukumoto, K. Kogawa, A. Shioi, and H. Morii The Fumagillin Analogue TNP-470 Inhibits DNA Synthesis of Vascular Smooth Muscle Cells Stimulated by Platelet-Derived Growth Factor and Insulin-like Growth Factor-I: Possible Involvement of Cyclin-Dependent Kinase 2 Circ. Res., October 1, 1996; 79(4): 757 - 764. [Abstract] [Full Text]
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J. Sadoshima and S. Izumo Rapamycin Selectively Inhibits Angiotensin II–Induced Increase in Protein Synthesis in Cardiac Myocytes In Vitro : Potential Role of 70-kD S6 Kinase in Angiotensin II– Induced Cardiac Hypertrophy Circ. Res., December 1, 1995; 77(6): 1040 - 1052. [Abstract] [Full Text]
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F. Peiretti, S. Lopez, P. Deprez-Beauclair, B. Bonardo, I. Juhan-Vague, and G. Nalbone Inhibition of p70S6 Kinase during Transforming Growth Factor-beta 1/Vitamin D3-induced Monocyte Differentiation of HL-60 Cells Allows Tumor Necrosis Factor-alpha to Stimulate Plasminogen Activator Inhibitor-1 Synthesis J. Biol. Chem., August 17, 2001; 276(34): 32214 - 32219. [Abstract] [Full Text] [PDF]
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M. J. Kluk and T. Hla Role of the Sphingosine 1-Phosphate Receptor EDG-1 in Vascular Smooth Muscle Cell Proliferation and Migration Circ. Res., September 14, 2001; 89(6): 496 - 502. [Abstract] [Full Text] [PDF]
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