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12,14-prostaglandin J2 and laminar fluid shear stress stabilize c-IAP1 in vascular endothelial cells
1Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582; 2Third Department of Internal Medicine, University of the Ryukyus School of Medicine, Okinawa 903-0215; 3Department of Pharmacology, National Cardiovascular Center Research Institute, Osaha 565-8565, Japan
Submitted 2 December 2002 ; accepted in final form 27 February 2003
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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12,14-prostaglandin J2
(15d-PGJ2) by elevating the expression level of lipocalin-type
prostaglandin D synthase. To investigate the role of 15d-PGJ2
produced in the vascular wall, we examined the effect of 15d-PGJ2
on endothelial cell apoptosis. We induced apoptosis in human umbilical vein
endothelial cells (HUVECs) by growth factor deprivation. 15d-PGJ2
strongly inhibited DNA ladder formation, nuclear fragmentation, and
caspase-3-like activity in HUVECs. To elucidate the mechanism by which
15d-PGJ2 inhibits endothelial cell apoptosis, we examined
expression of the inhibitor of apoptosis proteins (IAP) cellular-IAP1
(c-IAP1), c-IAP2, x-linked IAP, and survivin in HUVECs. In parallel with the
inhibition of apoptosis, 15d-PGJ2 elevated the expression level of
c-IAP1 protein in a dose- and time-dependent manner without changing the mRNA
level. Laminar shear stress also induced c-IAP1 expression. Chase experiments
with the use of cycloheximide revealed that 15d-PGJ2 and shear
stress both inhibited the proteolytic degradation of c-IAP1 protein. These
results suggested that 15d-PGJ2 inhibits endothelial cell apoptosis
through, at least in part, c-IAP1 protein stabilization. This mechanism might
be involved in the antiapoptotic effect of laminar shear stress.
apoptosis; troglitazone; peroxisome proliferator-activated receptor-
12-PGJ2, and
15-deoxy-12,14-PGJ2 (15d-PGJ2), are
natural ligands for peroxisome proliferator-activated receptor-
(PPAR), a ligand-activated transcription factor nuclear receptor
(9,
16). PPAR ligands,
including not only the PGJ2 family but also the thiazolidinedione
class of antidiabetic drugs, modulate several atherogenic processes. They
inhibit macrophage activation by inhibiting nitric oxide synthase gene
induction (27), the production
of inflammatory cytokines
(12), and the activation of
matrix metalloproteinase-9 (MMP-9)
(23). 15d-PGJ2 also
promotes the differentiation of macrophages by stimulating the expression of
scavenger receptor CD36 (25,
37). We reported that
PGJ2 and 12-PGJ2 strongly inhibit the
proliferation of vascular smooth muscle cells (VSMCs)
(30) and that
15d-PGJ2 induces G1 arrest and promotes differentiation
in VSMCs (24). PPAR
ligands including 15d-PGJ2 inhibit MMP-9 expression and
platelet-derived growth factor-BB-induced migration in VSMCs
(22). Moreover, they inhibit
the expression of vascular cell adhesion molecule-1 in endothelial cells
(11). Endothelial injury initiates atherogenesis. There are several mechanisms to protect endothelial cells from apoptotic death. One well-known mechanism is shear stress. Laminar fluid shear stress inhibits endothelial cell apoptosis and a lack of shear stress triggers apoptosis (6a). We previously reported that steady laminar shear stress stimulates endothelial cells to express lipocalin-type prostaglandin D synthase (35), which catalyzes the isomerization of PGH2 to produce PGD2 (38). PGs of the J2 family are naturally generated from PGD2 without specific enzymes (8, 31). In fact, we (35) detected PGD2 and 15d-PGJ2 from the culture medium of endothelial cells loaded with shear stress. Therefore, our results suggested that endothelial cells physiologically synthesize the PGJ2 family. As listed above, most of the effects elicited by the PGJ2 family seem to be atheroprotective. However, 15d-PGJ2 has been reported to promote apoptosis in ECV304, which is a so-called endothelial cell-derived cell line, and in human and bovine endothelial cells (3). Therefore, we decided to investigate whether 15d-PGJ2 really induces apoptosis in normal human endothelial cells with the use of human umbilical vein endothelial cells (HUVECs).
Recently, laminar shear stress has been reported to stimulate the gene expression of a member of the inhibitor of apoptosis protein (IAP) family, cellular IAP1 (c-IAP1) (13), which inhibits apoptosis by blocking caspases (6). Therefore, in the present study, we particularly focused on the role of the IAP family. Here, we report for the first time that 15d-PGJ2 and shear stress both induce c-IAP1 expression through protein stabilization and inhibit vascular endothelial cell apoptosis.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell culture and induction of apoptosis. HUVECs were obtained from human umbilical veins by collagenase digestion and was cultured in gelatin-coated dishes with DMEM containing 20% (vol/vol) FBS (GIBCO), 5 ng/ml human recombinant basic fibroblast growth factor (bFGF) (Amersham), 100 U/ml penicillin, 100 µg/ml streptomycin, and 1 µg/ml amphotericin B (growth medium) and were used for experiments in 80–90% confluence. Bovine aortic endothelial cells (BAECs) were grown in DMEM supplemented with 10% FBS, 100 U/ml penicillin, 100 µg/ml streptomycin, and 1 µg/ml amphotericin B. Apoptosis was induced by deprivation of bFGF for 24 h.
Shear stress apparatus. Steady laminar shear stress was loaded on endothelial cells grown on a gelatin-coated polyester sheet (Plastic Suppliers) in a parallel-plate flow chamber as described (1).
Nuclear staining. To detect nuclear fragmentation, both detached and adherent cells were harvested, fixed with 100 µl of 1% (vol/vol) glutaraldehyde for 30 min, and stained with 100 µM Hoechst 33258. The number of apoptotic cells was determined by observation of 1,000 cells with a fluorescent microscope.
DNA electrophoresis. To detect a DNA ladder, both detached and adherent cells were harvested and lysed in 100 µl of 10 mM Tris · HCl (pH 7.4) containing 10 mM EDTA (pH 8.0) and 0.5% Triton X-100 for 10 min on ice. After the addition of 40 µl of 10 mg/ml RNase, the cell lysate was incubated for 1 h at 37°C. Incubation was continued for 1 h after the addition of 2 µl of 20 mg/ml proteinase K. After incubation, DNA was extracted with 140 µl of phenol-chloroform-isoamyl alcohol [25:24:1 (vol/vol)] and then precipitated with ethanol and resolved in 5 µl of 10 mM Tris · HCl (pH 8.0) containing 1 mM EDTA (pH 8.0). Electrophoresis was carried out on a 2.0% agarose gel.
Caspase activity assay. Caspase-3-like activity was assayed by using a cysteine protease protein 32/caspase-3 colorimetric protease assay kit (Medical and Biological Laboratories; Nagoya, Japan). To detect caspase-3-like activity, endothelial cells were lysed on ice for 10 min. The cell lysate (100 µl) was incubated with 200 mM DEVD-p-nitroanilide at 37°C for 3 h. Absorbance at 405 nm was measured to determine the caspase-3-like activity.
Western blotting. Cells were lysed in 10 mM Tris · HCl (pH
7.4) containing 150 mM NaCl, 1 mM EDTA, 1% (vol/vol) Nonidet P-40, 0.1%
(wt/vol) sodium deoxycholate, 0.1% (wt/vol) SDS, 10 mM sodium fluoride, 200
µM Na3VO4, 20 µg/ml phenylmethylsulfonyl fluoride,
and 20 µg/ml leupeptin. The lysates were sonicated for 5 s and rocked on
ice for 1 h, followed by centrifugation at 16,000 g for 20 min to
remove insoluble pellets. Protein concentrations were determined by the
modified Lowry's method with a DC Protein Assay Kit (Bio-Rad). Proteins (20
µg/lane) were fractionated by SDS-PAGE, electroblotted onto a
polyvinylidene difluoride membrane, and immunoblotted with antibodies to human
c-IAP1 (Pharmingen International), c-IAP2 (Santa Cruz Biotechnology), x-linked
IAP (XIAP; R&D Systems), survivin (Santa Cruz Biotechnology), and
-tubulin (Calbiochem). Membranes were washed with Tween 20-Tris-buffered
saline (TTBS) and immunoblotted with second antibodies (horseradish
peroxidase-conjugated antibodies to mouse, rabbit, or goat immunoglobulins).
After being washed with TTBS, blots were visualized by using the enhanced
chemiluminescence Western blotting detection system (Amersham Pharmacia
Biotech).
RT-PCR. RT-PCR was performed with Ready-To-Go RT-PCR beads (Amersham Pharmacia Biotech). Total cellular RNAs (1 µg) were used for the RT reaction and the products were amplified by 30 thermal cycles with DNA Thermal Cycler 480 (Perkin-Elmer Cetus Instruments). PCR primers for human c-IAP1, c-IAP2, XIAP, survivin, and GAPDH were synthesized on the basis of the GenBank database (c-IAP1: 5'-TCAGAACACCGGAGGCATTTTC-3' and 5'-CCAGGATAGGAAGCACACATG-3'; XIAP: 5'-GCAGTTGGAAGACACAGGAAAG-3' and 5'-GATCCGTGCTTCATAATCTGCC-3'; survivin: 5'-TTTCTCAAGGACCACCGCATCT-3' and 5'-TTCCTAAGACATTGCTAAGGGGCC-3'; GAPDH: 5'-TCCACCACCCTGTTGCTGTA-3' and 5'-ACCACAGTCCATGCCATCAC-3').
Northern blotting. cDNAs for human c-IAP1, XIAP, and survivin were cloned by RT-PCR. cDNAs were labeled with 32P by a random primer DNA labeling kit (Takara Bio). Equal amounts of total cellular RNA (10 µg/lane) were resolved by electrophoresis on a 1% agarose gel containing 20 mM MOPS (pH 7.0), 5 mM sodium acetate, 0.5 mM EDTA, and 6% formaldehyde. After the gel was stained with ethidium bromide, RNA was transferred to a nylon membrane and fixed by means of ultraviolet irradiation. The membranes were incubated with cDNA probes in 50% formamide containing 10% polyethylene glycol, 7% SDS, 1 mM EDTA, 0.25 M NaCl, 0.25 M NaHPO4 (pH 7.2), and 100 µg/ml denatured salmon sperm DNA for 16 h at 50°C. They were washed with 30 mM NaCl containing 3 mM sodium citrate and 0.1% SDS at 65°C and analyzed with a BAS-2500 bioimage analyzer (Fuji).
Luciferase reporter assay. BAECs were cotransfected with a human
PPAR1 expression vector under the control of cytomegalovirus promoter
(pCMX-hPPAR1) (17) and
a luciferase expression vector containing thymidine kinase promoter and three
copies of rat acyl-CoA oxidase PPAR response element (tk-PPREx3-LUC)
(10), with the use of
TransIT-LT1 (Mirus). Simultaneously, a Renilla luciferase expression
vector (pRL-SV40; Toyo Ink) was also introduced as a control for transfection
efficiency. pCMX-hPPAR1 (150 ng), tk-PPREx3-LUC (150 ng), and pRL-SV40
(1 ng) were mixed with 50 µl of DMEM containing 1 µl of TransIT-LT1,
incubated at room temperature for 15 min, and then transfected into the cells.
After stimulation with PPAR ligands for 24 h, the luciferase activity
was determined with a luminometer and normalized with respect to
Renilla luciferase activity.
Statistics. Results are expressed as means ± SD of the number of observations. Statistical significance was assessed by Student's t-test.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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15d-PGJ2 inhibits endothelial cell apoptosis. Because shear stress stimulates endothelial cells to produce 15d-PGJ2 (35), we investigated the effect of 15d-PGJ2 on endothelial cell apoptosis. HUVECs were incubated in bFGF-deprived medium with various concentrations of 15d-PGJ2 for 24 h, and then DNA fragmentation was evaluated by electrophoresis. 15d-PGJ2 strongly inhibited the DNA fragmentation in a dose-dependent manner with a maximal effect at 16 µM (Fig. 1C). Concentrations >32 µM tended to be cytotoxic (not shown). Therefore, we used 16 µM of 15d-PGJ2 in the following experiments. 15d-PGJ2 inhibited DNA fragmentation throughout the time course examined (Fig. 1D).
Nuclear staining of HUVECs with Hoechst 33258 showed that bFGF deprivation induced a morphological change typical of apoptotic cells, which is nuclear fragmentation with condensed and bright chromatin (Fig. 2A,a). 15d-PGJ2 strongly inhibited this change (Fig. 2A,b).
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To confirm that 15d-PGJ2 inhibits HUVEC apoptosis, we further examined the effect of 15d-PGJ2 on the activity of caspase-3. bFGF deprivation markedly elevated caspase-3-like activity in HUVECs, but 15d-PGJ2 significantly reduced this activity (Fig. 2B).
15d-PGJ2 induces c-IAP1 protein expression. To identify the mechanism by which 15d-PGJ2 inhibits HUVEC apoptosis, we analyzed the expression of c-IAP1, c-IAP2, XIAP, and survivin by Western blot blotting. 15d-PGJ2 increased the expression level of c-IAP1 in a dose-dependent manner (Fig. 3A). c-IAP2 was not detected even after the treatment with 15d-PGJ2 (not shown). 15d-PGJ2 did not change the expression level of XIAP and decreased the expression level of survivin. In parallel with the inhibition of apoptosis (Fig. 1D), 15d-PGJ2 (16 µM) increased the expression level of c-IAP1 protein in a time-dependent manner (Fig. 3B).
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We then examined the mRNA expression of the IAP family by using RT-PCR (Fig. 3C). Although 15d-PGJ2 (16 µM) decreased the expression level of survivin mRNA in a time-dependent manner, 15d-PGJ2 did not change the mRNA levels of c-IAP1 and XIAP. The mRNA of c-IAP2 was not detected even after treatment with 15d-PGJ2, consistent with the result of Western blotting (not shown). To confirm the results of RT-PCR, we performed Northern blotting for c-IAP1, XIAP, and survivin (Fig. 3D). Although 15d-PGJ2 (16 µM) decreased the expression levels of survivin mRNA, 15d-PGJ2 did not change c-IAP1 and XIAP mRNA levels, consistent with RT-PCR.
15d-PGJ2 stabilizes c-IAP1 protein. To determine the mechanism by which 15d-PGJ2 increases c-IAP1 protein, we examined the effect of 15d-PGJ2 on the degradation of the protein. ALLN, a proteasome inhibitor, induced the expression of c-IAP1 protein in a dosedependent manner (Fig. 4A), suggesting that the expression was controlled by the ubiquitin-proteasome system, as shown by a previous report (39). Cycloheximide (CHX, 5 µM) completely inhibited the c-IAP1 expression induced by 15d-PGJ2, indicating that this concentration of CHX is able to completely inhibit the translation of c-IAP1 protein (Fig. 4B). After stimulation of HUVECs with ALLN for 24 h, we washed out ALLN and then immediately added CHX (5 µM) into the medium to block the new synthesis of c-IAP1 protein and incubated the cells with or without 15d-PGJ2 (16 µM) for the periods indicated (Fig. 4, C and D). Compared with CHX alone, 15d-PGJ2 significantly slowed the rate of degradation of c-IAP1 protein.
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Shear stress stabilizes c-IAP1 protein. Recently, Jin et al. (13) reported that laminar shear stress induces the gene expression of c-IAP1 in endothelial cells. In their study, shear stress transiently induced c-IAP1 mRNA with a maximal level being obtained at 4 h. However, they noticed that c-IAP1 protein continued to increase until 24 h, which could not be explained by the transient mRNA expression. Therefore, we examined whether shear stress also stabilizes c-IAP1 protein. Laminar shear stress certainly induced the expression of c-IAP protein, and this was completely inhibited by CHX (Fig. 5A). After exposure to shear stress to increase c-IAP1, HUVECs were cultured in the presence of CHX under static conditions or with shear stress (Fig. 5, B and C). As did 15d-PGJ2, shear stress also significantly slowed the degradation rate of c-IAP1 protein.
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Troglitazone inhibits endothelial cell apoptosis.
15d-PGJ2 may be the most effective endogenous ligand for
PPAR discovered to date
(9,
16). To examine whether the
antiapoptotic effect of 15d-PGJ2 occurred through a
PPAR-dependent pathway, we examined the effect of troglitazone, a
synthetic ligand for PPAR, on the apoptosis of HUVECs
(Fig. 6). First, we tested
whether 15d-PGJ2 and troglitazone really stimulate PPAR with
the use of BAECs, because DNA transfection efficiency was much higher in BAECs
than in HUVECs. We cotransfected the cells with tk-PPREx3-LUC and
pCMX-hPPAR1, because the elevation of luciferase activity was small
when we transfected tk-PPREx3-LUC alone. As shown in
Fig. 6A,
15d-PGJ2 markedly increased PPAR activity in a
dose-dependent manner. Troglitazone also increased PPAR activity in a
dose-dependent manner, although the effect was smaller than that of
15d-PGJ2. Then we examined the effect of troglitazone on HUVEC
apoptosis. As demonstrated in Fig.
6B, troglitazone significantly inhibited the DNA
fragmentation in a dose-dependent manner. Furthermore, troglitazone (50 µM)
also significantly elevated the expression level of c-IAP1
(Fig. 6C).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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activator, and overexpression of
PPAR also induced ECV304 apoptosis. On the basis of these results, they
concluded that 15d-PGJ2 induces endothelial cell apoptosis via a
PPAR-dependent pathway. In our study as well, ECV304 underwent apoptosis when cultured with 15d-PGJ2 (not shown). However, we cannot simply conclude that 15d-PGJ2 is proapoptotic for endothelial cells. First, ECV304 may not be an endothelial cell line. Certainly, ECV304 was considered to be a spontaneously transformed human vascular endothelial cell line (36), but recently it has been reported that this cell line was generated as a result of cross-contamination with the human bladder carcinoma cell line T-24 (21). If ECV304 is a nonendothelial cell line, it is no wonder that 15d-PGJ2 induces apoptosis, because this PG has been reported to induce apoptotic cell death in several other cell species, such as monocyte-derived macrophages (4), B lymphocytes (26), breast cancer cells (5), neuroblastoma cells (28), and colon cancer cells (32). Second, in their study (3), HUVECs also underwent apoptosis when treated with 15d-PGJ2, whereas in our study HUVECs were protected from apoptotic cell death at concentrations up to 16 µM. We do not know the reason for the discrepancy between their results and ours. Recently, Levonen et al. (19) reported that 15d-PGJ2 has biphasic effects on HUVEC apoptosis, i.e., low micromolar concentrations show a cytoprotective effect by inducing glutathione expression, whereas higher concentrations induce apoptosis. As they suggested, the cytotoxic effect of very high concentrations (32 µM or more) of 15d-PGJ2 may be caused by oxidative stress, because 15d-PGJ2 has been shown to activate MAP kinase cascades involving reactive oxygen species in astrocytes and preadipocytes (18).
We suggested that stabilization of c-IAP1 protein is one of the
antiapoptotic signals provoked by 15d-PGJ2. The IAP family proteins
are characterized by a highly conserved 
70 amino acid domain termed the
baculoviral inhibitory repeat (BIR), because the IAP family was originally
identified in baculoviruses
(6). These proteins regulate
programmed cell death in a wide variety of organisms
(7). The human IAP family
includes c-IAP1, c-IAP2, XIAP, survivin, and neuronal apoptosis inhibitory
protein (6). c-IAP1, c-IAP2,
and XIAP strongly inhibit the activity of caspases-3, -7, and -9. c-IAP1 and
XIAP are degraded by the ubiquitinproteasome system and inhibition of
proteasomes blocks the decrease in IAP expression induced by the apoptotic
stimuli (39). In addition to
the BIR domain, c-IAP1, c-IAP2, and XIAP contain a zinc-binding really
interesting new gene (RING) finger domain at the COOH-terminal end
(6). Ubiquitination of protein
is dependent on an intact RING finger
(20) and c-IAP1 and XIAP
catalyze their own ubiquitination in vitro and this reaction requires the RING
domain as well (39).
In our study, 15d-PGJ2 upregulated the expression of c-IAP1 protein through stabilization; however, XIAP was not upregulated by 15d-PGJ2 despite the presence of the RING finger domain. The reason for this difference is not clear. 15d-PGJ2 may not stabilize c-IAP1 protein simply via the RING finger domain. As to the mechanism of c-IAP1 stabilization by 15d-PGJ2, a recent report (34) shows that in a leukemia cell line, K562, which lacks tumor suppressor p53, externally introduced p21, a cyclin-dependent kinase inhibitor, inhibited the degradation of c-IAP1. Because p21 is induced by 15d-PGJ2 in VSMCs (24) and was also induced in HUVECs (not shown), c-IAP1 stabilization might be the result of p21 induction.
On the other hand, 15d-PGJ2 decreased both mRNA and protein expression levels of survivin. Survivin is unique among the IAP family, because it is expressed only in proliferating cells, particularly in growing tumors and developing organs (2). Present studies (33) suggest that survivin plays an important role as a regulator of cell proliferation rather than as a cytoprotective factor against apoptotic cell death. We reported that 15d-PGJ2 arrests the cell cycle in the G0/G1 phase in VSMCs (24), and we confirmed that 15d-PGJ2 also inhibited the proliferation of HUVECs in a dose-dependent manner (not shown). Therefore, 15d-PGJ2 may decrease the expression of survivin as a result of inhibition of HUVEC proliferation.
We (35) reported that endothelial cells produce 15d-PGJ2 in response to shear stress. Recently, Jin et al. (13) reported that shear stress induces the expression of c-IAP1 mRNA transiently and the protein continuously. We found that shear stress also slowed the rate of degradation of c-IAP1 protein, as did 15d-PGJ2. Although 15d-PGJ2 is not able to explain the transient transcriptional activation of c-IAP1 gene, this PG can contribute to the sustained expression level of c-IAP1 protein. Therefore, one mechanism by which shear stress inhibits endothelial cell apoptosis might be the production of 15d-PGJ2.
Troglitazone, a synthetic PPAR ligand, also inhibited HUVEC
apoptosis. The difference between the minimal concentrations of
15d-PGJ2 and troglitazone required to inhibit apoptosis (4 and 25
µM, respectively) may reflect the difference in their ability to stimulate
PPAR. Because troglitazone also induced expression of c-IAP1,
15d-PGJ2-induced c-IAP1 expression might be PPAR-dependent.
At this stage, however, we cannot exclude the possibility that the effect of
15d-PGJ2 is PPAR independent, because some of the effects
induced by 15d-PGJ2 and also synthetic PPAR ligands, such as
troglitazone, have been reported to be PPAR independent. For example,
15d-PGJ2 inhibits I
B kinase independently of PPAR
(29). Further study is needed
to determine whether PPAR is involved in the antiapoptotic effect of
15d-PGJ2.
In addition, the antiapoptotic effect 15d-PGJ2 produced in the vascular wall can exhibit several atheroprotective effects by modulating various processes in atherogenesis. 15d-PGJ2 or other substances of a similar nature may provide novel preventive and therapeutic strategies for the treatment of atherosclerotic vascular diseases.
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ACKNOWLEDGMENTS |
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expression vector. We also thank Sankyo for providing
troglitazone. This study was supported by Research Grants for Cardiovascular Diseases 11C-1 and 12C-3 from the Ministry of Health, Labour, and Welfare, Japan, a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and Mochida Memorial Foundation for Medical and Pharmaceutical Research, and a grant for Research on Hypertension and Vascular Metabolism from Japan Heart Foundation/Pfizer.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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, 15d-PGJ2; 
,
control.
, Shear stress; 
, static control.