Vascular Biology |
From the Division of Cardiovascular Research, St. Elizabeths Medical Center (M.S., T.S., K.W.), and the Program in Cell, Molecular, and Developmental Biology, Sackler School of Biomedical Sciences (K.W.), Tufts University, Boston, Mass; and the Department of Cardiovascular Medicine, Graduate School of Medicine (M.S.), University of Tokyo, Tokyo, Japan.
Correspondence to Dr Kenneth Walsh, Division of Cardiovascular Research, St. Elizabeths Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail kwalsh{at}opal.tufts.edu
| Abstract |
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(TNF-
) or interferon gamma (IFN-
). In contrast, VSMCs
expressed relatively high levels of Fas, and treatment with TNF-
or
IFN-
induced little or no upregulation under the conditions of these
assays. ECs were resistant to death after exposure to soluble
FasL or agonist anti-Fas antibody and also after infection with
Adeno-FasL in the presence or absence of cytokine treatment. In
contrast, VSMCs remained viable in the presence of soluble FasL or
agonist anti-Fas antibody, but they underwent apoptosis after
infection with Adeno-FasL. IFN-
enhanced Adeno-FasL-induced death of
VSMCs, but TNF-
did not. These findings provide insights about the
potential role of Fas-mediated apoptosis in the vessel wall and
suggest strategies to treat proliferative vascular diseases by
exploiting the differential sensitivity of ECs and VSMCs to
FasL-induced cell death.
Key Words: Fas adenovirus smooth muscle cells endothelial cells apoptosis
| Introduction |
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Numerous recent studies have examined the role of Fas-mediated cell
death in the vasculature.7 8 9 10 11 12 13 14 15 16 17 18 19 These studies have led to
conflicting hypotheses regarding the susceptibility of vascular cells
to Fas-mediated cell death and the expression of Fas-regulatory
components by vascular smooth muscle cells (VSMCs) and
endothelial cells (ECs). For example, it has been shown
that VSMCs undergo apoptosis both in vitro and in vivo after
infection with a replication-defective adenovirus expressing
FasL.13 18 However, another study found that VSMCs were
resistant to agonist anti-Fas antibody and that Fas-mediated
VSMC death occurred only after treatment with interferon gamma
(IFN
), interleukin-1ß, or TNF-
.10 Many of these
discrepancies may result from differences in experimental conditions,
the use of Fas agonists that may differ in their ability to transmit
death signals,20 21 or the use of commercial anti-FasL
antibody reagents that lack specificity for FasL.22 23 24 25
Owing to the potential importance of Fas-mediated cell death in
vascular disorders, we systematically examined Fas and FasL expression
by ECs and VSMCs and characterized the sensitivity of these cells to
Fas-mediated apoptosis by using multiple reagents. These
results document that ECs and VSMCs differ markedly in their expression
of Fas and FasL and in their sensitivity to FasL-induced cell death. It
might be possible to exploit these differences to develop strategies to
treat inflammatory-fibroproliferative disorders of the vessel wall.
| Methods |
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and human IFN-
were purchased from R&D Systems and Gibco BRL, respectively.
Adenoviral Constructs
A replication-defective adenoviral vector expressing murine FasL
from the cytomegalovirus promoter (Adeno-FasL) was constructed as
described.29 The Adeno-FasL lacks functional E1 and E3
regions. Viral titer was measured by standard plaque assay with 293
cells.
Flow Cytometry to Detect Fas or FasL Expression
To detect cell-surface expression of FasL, cells were detached
from the culture plate with 0.5% EDTA in PBS and washed with 10% FBS
in PBS. Cells were incubated with antibody (20 µg/mL) diluted with
1% BSA and 0.1% NaN3 in PBS at 4°C for 60
minutes. C-20 (rabbit IgG, Santa Cruz), clone 4H9 (hamster IgG, MBL),
clone A11 (rat IgM, Alexis), or clone Mike-1 (rat IgG, Alexis) was used
as an anti-FasL antibody. Isotype-matched nonspecific immunoglobulins
were used as negative controls. Cells were washed with 10 mmol/L
EDTA and 0.1% NaN3 in PBS and incubated with
FITC-conjugated secondary antibodies appropriate to the first
antibodies at 4°C for 60 minutes (1:100).
Immunofluorescence staining was analyzed by
a fluorescence-activated cell sorter (FACS, Becton
Dickinson). Cells were washed and fixed in freshly prepared 1%
paraformaldehyde. To analyze cell-surface
expression of Fas, cells were detached from the plates with 0.5% EDTA
and incubated with an FITC-conjugated anti-Fas mouse monoclonal
antibody (1:10, UB2, MBL) or an FITC-conjugated mouse IgG (Pharmingen).
Immunofluorescence staining was analyzed by
flow cytometry.
Detection of Apoptosis by Flow Cytometry
Cells were treated with either sFasL (500 ng/mL) for 24
hours, an agonistic anti-Fas antibody (500 ng/mL, CH11, MBL) for 24
hours, or Adeno-FasL (multiplicity of infection [MOI] 300) for 48
hours. Adherent cells were harvested by trypsinization and combined
with floating cells. Cells were fixed with 70% ethanol and stained
with propidium iodide, and DNA content was analyzed by flow
cytometry.12 Gating was set to exclude debris and cellular
aggregates, and 10 000 or more events were counted for each
analysis. All flow cytometric analyses were repeated
between 2 and 4 times with different preparations of hVSMCs and HUVECs.
Analyses of the effects of Adeno-FasL infection on VSMC
apoptosis and the cell cycle profile in 0.5% and 10% serum
was performed on parallel cultures at
40% confluence.
RT-PCR Analyses
Reverse transcriptasepolymerase chain reaction (RT-PCR) assays
were used to qualitatively assess FasL expression in HUVECs, hVSMCs,
and activated and nonactivated Jurkat cells. Total RNA
was isolated from HUVECs, hVSMCs, and activated and
nonactivated Jurkat cells. The RNA was then reverse-transcribed
to cDNA and amplified by PCR (TaKaRa RNA PCR kit), generating a 534-bp
fragment of FasL (forward primer:
5'-GTTCTGGTTGC-CTTGGTAGG-3'; reverse primer:
5'-GACCAGAGAGAGCTC-AGATACG-3') or a 983-bp fragment of
GAPDH (forward primer: 5'-TGAAGGTCGGAGTCAACGGATTTGGT-3'; reverse
primer: 5'-CATGTGGGCCATGAGGTCCACCAC-3'; Clontech). The following
conditions were used: 1 cycle at 94°C for 5 minutes and then 35
cycles at 95°C for 40 seconds, 58°C for 1 minute, and 72°C for
1.5 minutes. The PCR products were electrophoresed in a 2% agarose
gel. A plasmid containing the human FasL cDNA was used as a positive
control.
| Results |
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RT-PCR analysis was performed to assay for FasL transcripts in
vascular cells. Amplification products corresponding to FasL were
detected in HUVECs and, surprisingly, in hVSMCs (Figure 1C
). In
contrast, Jurkat cells were devoid of mRNA under nonstimulatory
conditions, but FasL mRNA expression could be detected in Jurkat cells
after stimulation with PMA and ionomycin as described
previously.23 32
Regulation of Fas Expression
Fas expression was analyzed on cultured HUVECs, hVSMCs,
and Jurkat cells with the monoclonal antibody UB2 that recognizes human
Fas (Figure 2
). Like rat
VSMCs,13 Fas was abundantly expressed on hVSMCs. Abundant
Fas expression was also detected on Jurkat cells, as reported by
others.20 Consistent with previous
studies,12 14 HUVECs expressed little or no Fas when
compared with hVSMCs and Jurkat cells.
|
Previous reports have documented that inflammatory cytokines
regulate Fas expression on VSMCs and ECs,8 10 14 and in
some cases, it has been proposed that upregulation of Fas will promote
vascular cell apoptosis.8 10 15 16 17 Therefore, to
understand the potential role of Fas expression in the differential
sensitivity of ECs and VSMCs to Fas-mediated apoptosis, we
systematically compared the effects of TNF-
and IFN-
on Fas
expression in HUVECs, hVSMCs, and Jurkat cells (Figure 2
). Under
the conditions of our assays, TNF-
modestly upregulated Fas
expression on HUVECs but had little or no effect on Fas expression by
hVSMCs or Jurkat cells. IFN-
markedly upregulated Fas expression on
ECs, consistent with a previous report,14 but
IFN-
had little or no effect on Fas expression by hVSMCs or Jurkat
cells.
Fas-mediated VSMC apoptosis has been implicated in cell
turnover in atherosclerotic plaque,8 10 and it has been
reported that plaque VSMCs express more Fas than do the underlying
medial VSMCs.10 Therefore, we tested whether Fas
expression might be different between quiescent hVSMCs cultured in
low-serum medium (0.5% FBS) and in proliferating hVSMCs cultured in
high-serum medium (10% FBS). As shown in Figure 3A
, quiescent and proliferating hVSMCs
expressed similar levels of cell-surface Fas.
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It is also reported that the adenovirus-encoded proteins E1B-19K or RID
(receptor internalizing and degradation) modulate sensitivity to
Fas-mediated apoptosis by affecting Fas expression on the
surface.33 Thus, cell-surface Fas levels were determined
after infection with Adeno-FasL to ascertain whether the previously
reported cytotoxic effects of Adeno-FasL on VSMCs13 18 is
modulated by a confounding effect of the viral genome on Fas
expression. Infection with Adeno-FasL produced little or no change in
Fas expression on hVSMCs (Figure 3B
). Similarly, Adeno-FasL had
no effect on HUVEC Fas expression (not shown).
Differential Sensitivity of Vascular ECs and VSMCs to
Fas-Mediated Apoptosis
The sensitivity of HUVECs, hVSMCs, Jurkat cells, or P815-huFas
mastocytoma cells to various anti-Fas agonists was analyzed
(Figure 4
). Cells were incubated with
sFasL, agonistic anti-Fas antibody (CH11), or Adeno-FasL (MOI 300).
Hypodiploid DNA content was analyzed by flow cytometry to
assess the extent of apoptotic cell death. No death was evident
when HUVECs were treated with any of these Fas agonists. In contrast,
P815-huFas or Jurkat cells readily underwent apoptosis after
treatment with sFasL, anti-Fas antibody, or Adeno-FasL. Despite
abundant Fas expression (Figures 2
and 3
), hVSMCs did not
undergo apoptosis on exposure to sFasL or anti-Fas antibody,
consistent with a previous report.10 However,
VSMCs underwent apoptosis after infection with Adeno-FasL
(Figure 4
), which produces membrane-bound FasL (Figure 1A
). Infection with a control adenovirus encoding
ß-galactosidase (Adenoß-gal) had no effect on the DNA profile
(Table 1
). These results indicate that
membrane-bound FasL, encoded by Adeno-FasL, is sufficient to trigger an
apoptotic signal in VSMCs, whereas Fas stimulation by
recombinant sFasL or agonistic anti-Fas antibody is not.
|
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Because cytokines can modulate the expression of Fas and
FasL10 12 14 and are reported to promote VSMC cell death
by agonist anti-Fas antibody,10 we examined the effects of
IFN-
or TNF-
treatment on the viability of HUVECs and hVSMCs that
were infected with Adeno-FasL. HUVECs failed to undergo
apoptosis with any treatment regimen tested (Figure 5
). Of note, HUVECs did not undergo
apoptosis after incubation with IFN-
and infection with
Adeno-FasL, which markedly upregulates cell-surface Fas (Figure 2
) and increases the expression of cell-surface FasL (Figure 1A
), respectively. TNF-
by itself appeared to induce
hypodiploid DNA formation in HUVECs, consistent with a previous
report on the cytotoxic action of this cytokine on
ECs.34 However, HUVEC apoptosis in the presence of
TNF-
was not enhanced by infection with Adeno-FasL (Figure 5
). In contrast to HUVECs, Adeno-FasL induced apoptosis
in hVSMCs in the presence or absence of IFN-
or TNF-
(Figure 5
). Although these cytokines had no effect on hVSMC
viability alone, IFN-
sensitized the cells toward the cytotoxic
action of Adeno-FasL, whereas TNF-
reduced Adeno-FasL
cytotoxicity.
|
Finally, hVSMCs cultured in 0.5% and 10% serum were compared for
their sensitivity to Adeno-FasLinduced cell death. The dose
responsiveness of VSMCs to Adeno-FasL is shown in Table 1
.
Quiescent, mitogen-deprived, and proliferating VSMCs were similar in
their sensitivity to Fas-mediated apoptosis resulting from
infection with Adeno-FasL. Analysis of cell cycle profiles
revealed that hVSMCs cultured in a high-serum medium displayed an
increased proportion of cells in G2/M phases when treated with low,
subtoxic doses of Adeno-FasL (Table 2
).
However, toxic doses of Adeno-FasL increased the fraction of VSMCs in
G0/G1 relative to controls. Under low-serum growth conditions,
infection with Adeno-FasL did not appear to alter the cell cycle
profile of hVSMCs. Furthermore, Adeno-FasL did not affect the cell
cycle distribution of HUVECs at any dose examined (data not shown).
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| Discussion |
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Previously, we reported that ECs express cell-surface FasL.12 Because the specificity of some commercial anti-FasL antibodies has come into question,22 23 24 25 FasL expression on HUVECs was analyzed by using 4 separate anti-FasL antibodies. All 4 antibodies detected cell-surface FasL expression on HUVECs by FACS analysis, but little or no signal was detected in cultures of hVSMCs or nonactivated Jurkat cells. Moreover, the FasL signal on HUVECs was increased after infection with Adeno-FasL and abrogated when anti-FasL antibody was incubated with excess, recombinant sFasL. In contrast to HUVECs, FasL expression was not detected on the cell surface of hVSMCs. Expression of FasL by HUVECs was also documented by RT-PCR analysis. Surprisingly, FasL mRNA was also detected in hVSMCs, suggesting that posttranscriptional control mechanisms may inhibit cell-surface expression of FasL protein in this cell type.
In contrast to FasL, Fas was abundantly expressed on the cell surface
of hVSMCs, but HUVECs expressed little or no cell-surface Fas compared
with VSMCs or Jurkat cells. Consistent with a previous
report,14 IFN-
markedly upregulated Fas expression on
HUVECs, whereas IFN-
treatment had relatively little effect on Fas
expression in hVSMCs or Jurkat cells. Treatment with TNF-
modestly
upregulated Fas expression on HUVECs but had little or no effect on Fas
expression by hVSMCs.
Infection with Adeno-FasL is sufficient to kill hVSMCs (Figure 4
) and rat VSMCs.13 35 In contrast, agonist
anti-Fas antibody (CH11) or recombinant sFasL had no effect on hVSMC
viability, but these compounds could induce apoptosis in Jurkat
cells or the P815-huFas mastocytoma cell line that overexpresses Fas.
The differential sensitivity of hVSMCs to adenovirus-encoded FasL
versus anti-Fas antibody or sFasL agonists may result from the ability
of cDNA delivery to produce membrane-bound FasL. It has been proposed
that membrane-bound FasL is presented to target cells in a
physiologically relevant manner, whereas
anti-Fas antibody and sFas agonists do not efficiently induce
apoptosis because of a lack of receptor
clustering.20 36
Geng et al10 reported that agonist anti-Fas antibody
could trigger hVSMC apoptosis only in the presence of IFN-
or TNF-
. Under the conditions of our assays, IFN-
increased hVSMC
apoptosis induced by infection with Adeno-FasL, but TNF-
protected hVSMCs from this death stimulus. The effects of these
cytokines on the susceptibility of hVSMCs to Fas-mediated cell
death is unlikely to result from alterations in receptor level, as
IFN-
or TNF-
did not appreciably modulate cell-surface Fas
expression in our assays. Presumably, these cytokines modulate
Fas-mediated VSMC apoptosis by regulating downstream components
of the death signaling pathway. Consistent with this
hypothesis, TNF-
induction of nuclear factor-
B has been reported
to protect cells from apoptosis.37 38 In related
experiments, we also found that mitogen stimulation did not affect
Fas-mediated apoptosis in hVSMCs. However, infection with
Adeno-FasL appeared to alter cell cycle kinetics when VSMCs were
cultured with high levels of serum.
Although ECs express Fas receptor on their cell surfaces, they do not
undergo apoptosis when exposed to sFasL or agonist anti-Fas
antibody,14 or when cell-surface Fas ligand is increased
by adenovirus-mediated FasL gene delivery. It is also notable that
infection with Adeno-FasL did not induce apoptosis in HUVECs in
the presence of IFN-
, which markedly increases Fas expression.
Presumably, ECs are normally resistant to Fas-mediated cell
death because they express endogenous cell-surface FasL and
therefore possess endogenous mechanisms that block the
transmission of the death signaling pathway after engagement of Fas by
FasL. The factors that confer EC resistance to Fas-mediated
apoptosis are currently unknown. One possibility is that the
Fas-mediated death signal in ECs is blocked by FLICE (Fas-associated
death domainlike interleukin-1ßconverting
enzyme)-inhibitory proteins (FLIPs).39 40 41
Consistent with this notion, FLIPs have been detected in
ECs42 and are downregulated by oxidized lipids, which
sensitize ECs to Fas-mediated apoptosis.7
The differential sensitivity of ECs and SMCs to Fas-mediated apoptosis may lead to the development of novel strategies to treat proliferative diseases of the vessel wall. On one hand, the cytotoxic action of FasL on proliferating VSMCs may have utility for the treatment of injury-induced intimal hyperplasia.13 18 In this application, FasL gene transfer might function as a potent suppressor of intimal hyperplasia because it is expressed on the VSMC surface, leading to the induction of cell death in a paracrine manner.13 Furthermore, FasL may augment the endogenous immunosuppressive properties of the vessel wall,12 18 yet it should not inhibit the beneficial process of reendothelialization, as ECs are normally resistant to Fas-mediated cell death. The resistance of ECs to Fas-mediated apoptosis may also allow the use of these cells as vehicles for the overexpression of exogenous FasL to inhibit lesions that develop in the vessels of allografted organs.43 These vascular lesions are associated with the early infiltration of T lymphocytes and macrophages in the subendothelial space,44 followed by a gradual increase in the presence of VSMCs in the intima.45 Therefore, inhibition of this early inflammatory response at the endothelial surface by the elevated expression of FasL could have utility in reducing the chronic vascular graft disease that develops within transplanted organs.
| Acknowledgments |
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Received April 1, 1999; accepted September 15, 1999.
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K. Selvendiran, L. Tong, S. Vishwanath, A. Bratasz, N. J. Trigg, V. K. Kutala, K. Hideg, and P. Kuppusamy EF24 Induces G2/M Arrest and Apoptosis in Cisplatin-resistant Human Ovarian Cancer Cells by Increasing PTEN Expression J. Biol. Chem., September 28, 2007; 282(39): 28609 - 28618. [Abstract] [Full Text] [PDF] |
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Y. Li, Y.-H. Song, J. Mohler, and P. Delafontaine ANG II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H2116 - H2123. [Abstract] [Full Text] [PDF] |
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C. Hasel, S. Durr, A. Bauer, R. Heydrich, S. Bruderlein, T. Tambi, U. Bhanot, and P. Moller Pathologically elevated cyclic hydrostatic pressure induces CD95-mediated apoptotic cell death in vascular endothelial cells Am J Physiol Cell Physiol, August 1, 2005; 289(2): C312 - C322. [Abstract] [Full Text] [PDF] |
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L. A. Smyth and H. J.M. Brady cMet and Fas Receptor Interaction Inhibits Death-Inducing Signaling Complex Formation in Endothelial Cells Hypertension, July 1, 2005; 46(1): 100 - 106. [Abstract] [Full Text] [PDF] |
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N. Askenasy, E. S. Yolcu, I. Yaniv, and H. Shirwan Induction of tolerance using Fas ligand: a double-edged immunomodulator Blood, February 15, 2005; 105(4): 1396 - 1404. [Abstract] [Full Text] [PDF] |
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S. V. Ashton, G. St. J. Whitley, P. R. Dash, M. Wareing, I. P. Crocker, P. N. Baker, and J. E. Cartwright Uterine Spiral Artery Remodeling Involves Endothelial Apoptosis Induced by Extravillous Trophoblasts Through Fas/FasL Interactions Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 102 - 108. [Abstract] [Full Text] [PDF] |
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W. C. Chan, T. T. Duong, and R. S. M. Yeung Presence of IFN-{gamma} Does Not Indicate Its Necessity for Induction of Coronary Arteritis in an Animal Model of Kawasaki Disease J. Immunol., September 1, 2004; 173(5): 3492 - 3503. [Abstract] [Full Text] [PDF] |
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J. Yang, K. Sato, T. Aprahamian, N. J. Brown, J. Hutcheson, A. Bialik, H. Perlman, and K. Walsh Endothelial Overexpression of Fas Ligand Decreases Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1466 - 1473. [Abstract] [Full Text] [PDF] |
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K. Wallner, C. Li, P. K. Shah, K.-J. Wu, S. M. Schwartz, and B. G. Sharifi EGF-Like Domain of Tenascin-C Is Proapoptotic for Cultured Smooth Muscle Cells Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1416 - 1421. [Abstract] [Full Text] [PDF] |
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C. Skurk and K. Walsh Death Receptor Induced Apoptosis: A New Mechanism of Homocysteine-Mediated Endothelial Cell Cytotoxicity Hypertension, June 1, 2004; 43(6): 1168 - 1170. [Full Text] [PDF] |
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Y. Takemura, K. Fukuo, O. Yasuda, T. Inoue, N. Inomata, T. Yokoi, H. Kawamoto, T. Suhara, and T. Ogihara Fas Signaling Induces Akt Activation and Upregulation of Endothelial Nitric Oxide Synthase Expression Hypertension, April 1, 2004; 43(4): 880 - 884. [Abstract] [Full Text] [PDF] |
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Md. R. Abid, S. Guo, T. Minami, K. C. Spokes, K. Ueki, C. Skurk, K. Walsh, and W. C. Aird Vascular Endothelial Growth Factor Activates PI3K/Akt/Forkhead Signaling in Endothelial Cells Arterioscler Thromb Vasc Biol, February 1, 2004; 24(2): 294 - 300. [Abstract] [Full Text] |
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C. Skurk, H. Maatz, H.-S. Kim, J. Yang, M. R. Abid, W. C. Aird, and K. Walsh The Akt-regulated Forkhead Transcription Factor FOXO3a Controls Endothelial Cell Viability through Modulation of the Caspase-8 Inhibitor FLIP J. Biol. Chem., January 9, 2004; 279(2): 1513 - 1525. [Abstract] [Full Text] [PDF] |
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P. Justo, C. Lorz, A. Sanz, J. Egido, and A. Ortiz Intracellular Mechanisms of Cyclosporin A-Induced Tubular Cell Apoptosis J. Am. Soc. Nephrol., December 1, 2003; 14(12): 3072 - 3080. [Abstract] [Full Text] [PDF] |
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S. S Vasudevan, N. H.M Lopes, P. N Seshiah, T. Wang, C. B Marsh, D. J Kereiakes, C. Dong, and P. J Goldschmidt-Clermont Mac-1 and Fas activities are concurrently required for execution of smooth muscle cell death by M-CSF-stimulated macrophages Cardiovasc Res, September 1, 2003; 59(3): 723 - 733. [Abstract] [Full Text] [PDF] |
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J. Yang, S. P. Jones, T. Suhara, J. J. M. Greer, P. D. Ware, N. P. Nguyen, H. Perlman, D. P. Nelson, D. J. Lefer, and K. Walsh Endothelial Cell Overexpression of Fas Ligand Attenuates Ischemia-Reperfusion Injury in the Heart J. Biol. Chem., April 18, 2003; 278(17): 15185 - 15191. [Abstract] [Full Text] [PDF] |
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N. Askenasy, E. S. Yolcu, Z. Wang, and H. Shirwan Display of Fas Ligand Protein on Cardiac Vasculature as a Novel Means of Regulating Allograft Rejection Circulation, March 25, 2003; 107(11): 1525 - 1531. [Abstract] [Full Text] [PDF] |
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J. H. Li, M. S. Kluger, L. A. Madge, L. Zheng, A. L. M. Bothwell, and J. S. Pober Interferon-{gamma} Augments CD95(APO-1/Fas) and Pro-Caspase-8 Expression and Sensitizes Human Vascular Endothelial Cells to CD95-Mediated Apoptosis Am. J. Pathol., October 1, 2002; 161(4): 1485 - 1495. [Abstract] [Full Text] [PDF] |
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E. Lorenzo, C. Ruiz-Ruiz, A. J. Quesada, G. Hernandez, A. Rodriguez, A. Lopez-Rivas, and J. M. Redondo Doxorubicin Induces Apoptosis and CD95 Gene Expression in Human Primary Endothelial Cells through a p53-dependent Mechanism J. Biol. Chem., March 22, 2002; 277(13): 10883 - 10892. [Abstract] [Full Text] [PDF] |
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T. Suhara, H.-S. Kim, L. A. Kirshenbaum, and K. Walsh Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation Mol. Cell. Biol., January 15, 2002; 22(2): 680 - 691. [Abstract] [Full Text] [PDF] |
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M. Sata, S. Sugiura, M. Yoshizumi, Y. Ouchi, Y. Hirata, and R. Nagai Acute and Chronic Smooth Muscle Cell Apoptosis After Mechanical Vascular Injury Can Occur Independently of the Fas-Death Pathway Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1733 - 1737. [Abstract] [Full Text] [PDF] |
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C. Zietz, U. Rumpler, M. Sturzl, and U. Lohrs Inverse Relation of Fas-Ligand and Tumor-Infiltrating Lymphocytes in Angiosarcoma : Indications of Apoptotic Tumor Counterattack Am. J. Pathol., September 1, 2001; 159(3): 963 - 970. [Abstract] [Full Text] [PDF] |
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A. J. Belanger, A. Scaria, H. Lu, J. A. Sullivan, S. H. Cheng, R. J. Gregory, and C. Jiang Fas ligand/Fas-mediated apoptosis in human coronary artery smooth muscle cells: therapeutic implications of fratricidal mode of action Cardiovasc Res, September 1, 2001; 51(4): 749 - 761. [Abstract] [Full Text] [PDF] |
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M. Sata, Z. Luo, and K. Walsh Fas Ligand Overexpression on Allograft Endothelium Inhibits Inflammatory Cell Infiltration and Transplant-Associated Intimal Hyperplasia J. Immunol., June 1, 2001; 166(11): 6964 - 6971. [Abstract] [Full Text] [PDF] |
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A. Tedgui and Z. Mallat Anti-Inflammatory Mechanisms in the Vascular Wall Circ. Res., May 11, 2001; 88(9): 877 - 887. [Abstract] [Full Text] [PDF] |
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F. Aoudjit and K. Vuori Matrix Attachment Regulates FAS-Induced Apoptosis in Endothelial Cells: A Role for C-Flip and Implications for Anoikis J. Cell Biol., February 5, 2001; 152(3): 633 - 644. [Abstract] [Full Text] [PDF] |
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S. A. Fisher, B. L. Langille, and D. Srivastava Apoptosis During Cardiovascular Development Circ. Res., November 10, 2000; 87(10): 856 - 864. [Abstract] [Full Text] [PDF] |
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K. Walsh, R. C. Smith, and H.-S. Kim Vascular Cell Apoptosis in Remodeling, Restenosis, and Plaque Rupture Circ. Res., August 4, 2000; 87(3): 184 - 188. [Full Text] [PDF] |
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G. H. Gibbons and M. J. Pollman Death Receptors, Intimal Disease, and Gene Therapy : Are Therapies That Modify Cell Fate Moving too Fas? Circ. Res., May 26, 2000; 86(10): 1009 - 1012. [Full Text] [PDF] |
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M. Hernandez, L. Fuentes, F. J. Fernandez Aviles, M. S. Crespo, and M. L. Nieto Secretory Phospholipase A2 Elicits Proinflammatory Changes and Upregulates the Surface Expression of Fas Ligand in Monocytic Cells: Potential Relevance for Atherogenesis Circ. Res., January 11, 2002; 90(1): 38 - 45. [Abstract] [Full Text] [PDF] |
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T. Suhara, T. Mano, B. E. Oliveira, and K. Walsh Phosphatidylinositol 3-Kinase/Akt Signaling Controls Endothelial Cell Sensitivity to Fas-Mediated Apoptosis via Regulation of FLICE-Inhibitory Protein (FLIP) Circ. Res., July 6, 2001; 89(1): 13 - 19. [Abstract] [Full Text] [PDF] |
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