Published online before print June 9, 2008, doi: 10.1161/CIRCULATIONAHA.107.746453
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(Circulation. 2008;117:3079-3087.)
© 2008 American Heart Association, Inc.
Molecular Cardiology |
Critical Role of Bone Marrow Apoptosis-Associated Speck-Like Protein, an Inflammasome Adaptor Molecule, in Neointimal Formation After Vascular Injury in Mice
From the Departments of Cardiovascular Medicine (N.Y., M.T., H.M., Y.S., H.I., U.I.) and Molecular Oncology (Y.T., J.S., S.T.), Shinshu University Graduate School of Medicine, and Department of Pathology (J.M., J.N.), Shinshu University School of Medicine, Matsumoto, Japan.
Correspondence to Masafumi Takahashi, MD, PhD, Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. E-mail masafumi{at}shinshu-u.ac.jp
Received June 12, 2007; accepted March 31, 2008.
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Abstract |
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Background— Inflammatory cytokines such as interleukin (IL)-1β and IL-18 play an important role in the development of atherosclerosis and restenosis. Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is an adaptor protein that regulates caspase-1–dependent IL-1β and IL-18 generation; however, the role of ASC in vascular injury remains undefined. Here, we investigated the contribution of ASC to neointimal formation after vascular injury in ASC-deficient (ASC–/–) mice.
Methods and Results— Wire-mediated vascular injury was produced in the femoral artery of ASC–/– and wild-type mice. Immunohistochemical analysis revealed that ASC was markedly expressed at the site of vascular injury. Neointimal formation was significantly attenuated in ASC–/– mice after injury. IL-1β and IL-18 were expressed in the neointimal lesion in wild-type mice but showed decreased expression in the lesion of ASC–/– mice. To investigate the contribution of bone marrow–derived cells, we developed bone marrow–transplanted mice and found that neointimal formation was significantly decreased in wild-type mice in which bone marrow was replaced with ASC–/– bone marrow cells. Furthermore, in vitro experiments showed that the proliferation activity of ASC–/– vascular smooth muscle cells was not impaired.
Conclusions— These findings suggest that bone marrow–derived ASC is critical for neointimal formation after vascular injury and identify ASC as a novel therapeutic target for atherosclerosis and restenosis.
Key Words: angioplasty • bone marrow cell • cytokine • inflammation • restenosis
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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Neointimal formation after vascular injury is the pathological basis of atherosclerosis and restenosis after percutaneous coronary intervention such as angioplasty and stenting. Although the pathogenic mechanisms have not been completely resolved, an accumulating body of evidence suggests that inflammatory response plays a key role in these processes. Interleukin (IL)-1β and IL-18, inflammatory cytokines that mediate a wide range of immune and inflammatory responses,1 have been shown to be involved in the development of restenosis and atherosclerosis.2–4 Generation of mature IL-1β and IL-18 requires proteolytic processing of IL-1β and IL-18 precursors by the converting enzyme caspase-1 (also known as IL-1β–converting enzyme).1 Recent studies have suggested that caspase-1 is activated within a multiple adaptor complex called the inflammasome complex.5 Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), also known as target of methylation-induced silencing-1,6 is a putative component of the inflammasome complex. We originally identified ASC as an intracellular protein that generates speck-like aggregations in apoptotic HL-60 cells treated with chemotherapeutic agents.7 ASC is a 21.5-kDa cytosolic protein that carries a caspase recruitment domain at the C-terminal and a domain (PYD) homologous to pyrin, a gene product responsible for familial Mediterranean fever, which is an inherited systemic disease characterized by recurrent episodes of fever and inflammation, at the N-terminal.8 ASC serves as a molecular bridge between PYD and caspase recruitment domain–containing signaling molecules. In addition, we and other investigators recently demonstrated that ASC mediates the recruitment and activation of caspase-1, thereby regulating caspase-1–mediated maturation of IL-1β and IL-18.9,10 Therefore, we hypothesized that ASC can regulate inflammation and subsequent neointimal formation at the site of vascular injury.
Editorial p 3060
Clinical Perspective p 3087
In the present study, we investigated the effect of ASC deficiency on neointimal formation after vascular injury in mice. Furthermore, because no information is available on the cell-specific role of ASC in vascular injury, we used the irradiation/bone marrow transplantation (BMT) model and found that bone marrow–derived ASC is critical for neointimal formation after vascular injury. Our study findings provide new insight into the role of ASC in the pathogenesis of atherosclerosis and restenosis and identify ASC as a novel therapeutic target for cardiovascular diseases.
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Materials and Methods |
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Animals
The animal experimental protocol used in this study was reviewed and approved by the Shinshu University Guide for Laboratory Animals, which conforms to the National Institutes of Health (NIH) guidelines. ASC–/– mice were generated as described previously9 and backcrossed to the C57BL/6 strain mice for 8 generations. These mice were maintained in our animal care facility and intercrossed with the C57BL/6 strain mice. The resulting littermates were used for this study (wild-type: ASC+/+ littermates and homozygous ASC–/– mice, male, 8 to 12 weeks old). Other wild-type mice (C57BL/6, male, 8 to 12 weeks old) were purchased from Japan SLC Inc. (Hamamatsu, Japan). They were fed a standard diet and water and were maintained on a 12-hour light/dark cycle.
Wire-Mediated Vascular Injury
Wire-mediated vascular injury of the right femoral artery was produced as described previously by Sata et al.11 We confirmed that this procedure induced reproducible neointimal formation in 8- to 12-week-old C57BL/6 mice.12
BMT Mice
BMT mice were produced as described previously.12 Whole bone marrow cells from wild-type and ASC–/– mice were harvested by flushing their femurs with PBS. Red blood cells were lysed with ACK buffer (150 mmol/L NH4Cl, 10 mmol/L KHCO3, 0.1 mmol/L EDTA, pH 7.2) at 4°C for 20 minutes. The cells were washed 3 times with PBS and resuspended in 0.5 mL PBS. Recipient mice (wild-type and ASC–/– mice, 6 to 8 weeks old) were lethally irradiated with a total dose of 9 Gy (MBR-155R2, Hitachi, Japan) and injected with bone marrow cells through the tail vein. To verify the reconstitution of bone marrow after transplantation by this protocol, we used green fluorescent protein–transgenic mice (C57BL/6 background, kindly provided by Professor M. Okabe, Osaka, Japan) as donors. Flow cytometry analysis revealed that at 6 weeks after transplantation, peripheral blood cells consisted of >90% green fluorescent protein–positive cells (Figure I of the online Data Supplement). Using this protocol, we produced 3 types of BMT mice: wild-type to wild-type (BMTWild
Wild) mice, wild-type to ASC–/– (BMTWildASC–/–) mice, and ASC–/– to wild-type (BMTASC–/–Wild) mice.
Histology and Immunohistochemistry
Histology and immunohistochemistry were performed as described previously.13 Details are given in the online Data Supplement. We confirmed the detection of reendothelialization after injury by using antibodies against CD31 and VE-cadherin (supplemental Figure II).
In Situ Hybridization
A digoxigenin-labeled RNA probe was prepared, and in situ hybridization was performed as described previously.14 Details are given in the online Data Supplement.
Detection of Apoptosis
Apoptotic cells were identified by the terminal transferase-mediated dUTP nick-end labeling (TUNEL) staining kit (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions.
Cell Cultures
Bone marrow cells were collected from wild-type and ASC–/– mice and analyzed by flow cytometry and Western blotting. Murine vascular smooth muscle cells (VSMCs) were isolated from the aorta of 4- to 6-week-old wild-type and ASC–/– mice and cultured in DMEM (Sigma, St Louis, Mo) supplemented with 10% FBS (Hyclone, Logan, Utah).15 VSMCs with 3 to 6 passages were used in the experiments.
Flow Cytometry Analysis
Blood samples were collected from the mice at baseline and 48 hours after vascular injury. Circulating cells were identified using a nucleated cell fraction. The cells were double labeled with FITC-conjugated anti-CD34 (clone RAM34, BD Biosciences, San Jose, Calif) and PE-conjugated anti–Flk-1 (VEGFR2/KDR: clone Avas12
1, BD Biosciences) antibodies and examined by flow cytometry. To identify ASC expression in blood cells, peripheral blood cells were collected and permeabilized with an intracellular antigen detection kit (Cytofix/Cytoperm, BD Biosciences) according to the manufacturer’s instructions. The nucleated cells were double labeled with anti-ASC antibody (generated as described previously9) and anti-CD11b (Mac-1: clone M1/70, BD Biosciences), anti-Gr-1 (BD Biosciences), or anti-CD3 (BD Biosciences) antibody. The cells were examined by flow cytometer (FACSCalibur, BD Biosciences) and analyzed with CellQUEST software version 3.3 (BD Biosciences).
Western Blot Analysis
Expression of ASC, extracellular-regulated kinase 1/2 (ERK1/2), p38, phospho-ERK1/2, and phospho-p38 was analyzed by Western blotting.9,16 The antibodies against phospho-ERK1/2 and phospho-p38 were purchased from Promega Corp (Madison, Wis), and the antibodies against phospho-ERK1/2 and p38 were purchased from Cell Signaling Technology, Inc (Danvers, Mass). The expression level of β-actin served as an internal control for protein loading.
VSMC Proliferation
VSMCs (1x104 per well) were cultured on 96-well plates, incubated in DMEM (Sigma) without serum for 16 hours, and then treated with or without recombinant human IL-1β (Genzyme/Techne, Minneapolis, Minn), recombinant mouse IL-18 (MBL, Nagoya, Japan), or platelet-derived growth factor-BB (PDGF-BB; Pepro-Tech, Inc, Rocky Hill, NJ) for 24 hours. The proliferation activity of VSMCs was determined by the uptake of BrdU with a cell proliferation ELISA kit (Roche Diagnostics, Mannheim, Germany) according to the manufacturer’s instructions.
Statistical Analysis
Data are expressed as mean±SEM. The unpaired 2-tailed t test was used to compare the 2 groups. For comparisons between multiple groups, we determined the significance of the difference between the means of the groups by 1-way ANOVA followed by the Tukey-Kramer procedure. All analyses were performed with EXSAS software (version 5.0, Arm Co, Ltd, Osaka, Japan). Differences with values of P<0.05 were considered statistically significant.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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ASC Expression After Vascular Injury
We first examined whether ASC was expressed in the vascular wall after injury. Immunohistochemistry revealed that the expression of ASC was clearly observed in the injured site at 7 days and in the neointimal lesion at 21 days after injury (Figure 1A). In contrast, we observed expression of ASC in the endothelium of the intact artery. To identify the cells that express ASC in the neointima, we performed double immunofluorescence staining using antibodies against ASC and macrophages (F4/80) or VSMCs (
-smooth muscle actin [-SMA]) and found that ASC was colocalized with macrophages or VSMCs (Figure 1B). Furthermore, in situ hybridization revealed the expression of ASC mRNA in the vascular wall after injury (Figure 1C).
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Effect of ASC Deficiency on Neointimal Formation
Because we previously demonstrated that neointimal formation is completed at 21 days after injury,12,13 we evaluated the effect of ASC deficiency on neointimal formation at 21 days after vascular injury. Hematoxylin and eosin and elastica–van Gieson staining revealed that the neointimal formation was markedly reduced in ASC–/– mice compared with wild-type mice (Figure 2A). Quantitative analysis showed that the neointimal area and the intima-to-media ratio were significantly reduced in ASC–/– mice (P=0.002 and P=0.007, respectively; Figure 2B and 2D). However, no significant difference was observed in the medial area between wild-type and ASC–/– mice (P=0.300; Figure 2C).
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IL-1β and IL-18 Expression and Apoptosis
Because ASC regulates the maturation of IL-1β and IL-18,5,9 we performed immunohistochemical analysis to detect IL-1β and IL-18 in the injured arteries. As shown in Figure 3A, IL-1β and IL-18 were expressed in the neointimal lesions of wild-type mice but showed decreased expression in the lesions of ASC–/– mice.
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To assess the involvement of apoptosis after vascular injury in wild-type and ASC–/– mice, TUNEL staining was performed. Consistent with a previous report,11 a substantial number of TUNEL-positive cells were detected in the vascular wall at 2 hours after injury in wild-type and ASC–/– mice (Figure 3B). Quantitative analysis showed no significant difference in TUNEL-positive cells between these mice. Furthermore, the expression of activated caspase-3 also was detected in the vascular wall after injury of both wild-type and ASC–/– mice (supplemental Figure III).
Detection of Endothelial Cells, Macrophages, and VSMCs
Because we previously demonstrated that early reendothelialization after vascular injury results in attenuation of neointimal formation,12 immunohistochemical analysis of the endothelial marker CD31 and VE-cadherin was performed. No significant difference was observed in reendothelialization at 7 days after injury between wild-type and ASC–/– mice (Figure 4A and 4B). Flow cytometry analysis also showed no difference in the number of peripheral CD34+/Flk-1+ cells (ordinary endothelial progenitor cell marker12,17) at 24 hours after vascular injury between wild-type and ASC–/– mice (wild-type, 0.015±0.005%; ASC–/–, 0.007±0.003%; P=NS). We further performed immunohistochemical analysis to detect macrophages (F4/80) and VSMCs (-SMA) and assessed the cellular contents of neointima in wild-type and ASC–/– mice. Consistent with previous reports,11,13 the neointimal lesion was composed of substantial number of VSMCs and some macrophages (Figure 4C through 4F). Although the total number of VSMCs and macrophages in the neointima of ASC–/– mice tended to be lower than that in the neointima of wild-type mice (Figure 4C and 4E), the number of VSMCs and macrophages per unit of the neointimal area did not differ between wild-type and ASC–/– mice (Figure 4D and 4F).
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Contribution of Bone Marrow–Derived Cells
To determine the contribution of bone marrow–derived cells to the attenuation of neointimal formation after vascular injury, we produced 3 types of BMT mice (BMTWildWild mice, BMTWildASC–/– mice, and BMTASC–/–Wild mice) and evaluated neointimal formation after injury. The formation of neointima after vascular injury in BMTWildWild mice was similar to that in wild-type mice, and it tended to be reduced in BMTWildASC–/– mice (Figure 5). Importantly, neointimal formation in BMTASC–/–Wild mice was markedly reduced compared with that in BMTWildASC–/– mice (intima-to-media ratio; P=0.0003) and BMTWildWild mice (P=0.015). These results indicate that bone marrow–derived ASC is critical for neointimal formation after injury. We also examined whether bone marrow–derived cells contribute to the neointimal lesion in BMT mice in which bone marrow was replaced with that of green fluorescent protein–transgenic mice and detected some green fluorescent protein–positive cells among the -SMA–positive cells (11.2±2.8%) in the neointimal lesion after injury (supplemental Figure IV).
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ASC Expression in Bone Marrow–Derived Cells
To determine the types of bone marrow–derived blood cells that express ASC, peripheral nuclear cells were analyzed by flow cytometry. The expression of ASC was detected in CD3+ cells (T cells), Mac-1+/Gr-1– cells (monocytes), and Gr-1+ cells (granulocytes) (Figure 6A through 6C). In particular, the expression of ASC in T cells showed 2 peaks of high and low expression. We further examined whether ASC-expressing cells were affected by the vascular injury and found that the injury had no significant effect on the percentage of ASC-expressing cells (day 1: CD3+ cells, 55.4±13.4% versus 48.2±12.1%; Mac-1+/Gr-1– cells, 31.5±6.7% versus 21.3±10.4%; Gr-1+ cells, 24.0±4.7% versus 12.4±5.4%; P=NS). Western blot analysis also confirmed ASC expression in bone marrow cells isolated from wild-type mice but not in those from ASC–/– mice (Figure 6D).
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Proliferation Activity of VSMCs
Neointimal lesion after vascular injury mainly comprises proliferative VSMCs.11 Because the mitogen-activated protein kinase pathway is thought to be critical for the VSMC proliferation signal,18 the effect of serum or growth factor on ERK1/2 and p38 activation in cultured VSMCs isolated from ASC–/– mice was investigated. Western blot analysis revealed marked phosphorylation of ERK1/2 and p38 in response to FBS and PDGF-BB in wild-type–derived VSMCs (Figure 7A and 7B). The PDGF-BB–induced phosphorylation of ERK1/2 and p38 reached a peak at 5 minutes and subsequently declined. In the ASC–/–-derived VSMCs, a similar phosphorylation pattern of ERK1/2 and p38 was observed. We further examined the proliferation activity of cultured VSMCs isolated from ASC–/– mice by using the BrdU incorporation assay. Treatment with PDGF-BB but not IL-1β and IL-18 stimulated proliferation in both wild-type–derived and ASC–/–-derived VSMCs, and no significant difference was observed in the activity between these VSMCs (Figure 7C). To determine cell proliferation activity in vivo, we performed immunohistochemical staining for proliferating cell nuclear antigen and found that the number of proliferating cell nuclear antigen–positive cells decreased in the neointimal lesion of ASC–/– mice (Figure 7D).
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Discussion |
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The major findings of this study are as follows: (1) ASC was markedly expressed at the site of vascular injury; (2) ASC deficiency reduced the expression of IL-1β and IL-18 in the neointimal lesion and attenuated neointimal formation after vascular injury; (3) the absence of ASC specifically in bone marrow cells reduced neointimal formation; and (4) the proliferation activity of ASC-deficient VSMCs was not impaired in in vitro experiments. These findings suggest that bone marrow–derived ASC plays a critical role in neointimal formation after vascular injury.
ASC is an adaptor molecule that mediates inflammatory and apoptotic signals. Recent investigations suggest that the PYD domain of ASC functions as the signal transduction/oligomerization domain, whereas the caspase recruitment domain functions as the effector domain for activation of caspase-1, thereby regulating the expression of IL-1β and IL-18.6 Accumulating reports have demonstrated the important role of ASC in the fields of immunology and oncology5,6,10,19,20; however, to date, no information is available on the role of ASC in cardiovascular diseases. In the present study, we clearly demonstrated that neointimal formation and expression of IL-1β and IL-18 after vascular injury were attenuated in ASC–/– mice. Furthermore, we recently observed the expression of ASC in human atherosclerotic lesions (M. Takahashi and J. Nakayama, unpublished observation, 2008); this suggests the potential role of ASC and its downstream cytokines in neointimal formation. Indeed, several lines of evidence indicate that IL-1β and IL-18 play an important role in the pathogenesis of atherosclerosis and restenosis after percutaneous coronary intervention. For instance, increased expression of IL-1β and IL-18 has been reported in human atherosclerotic plaques.4,21 Genetic correlations between IL-1 genotype and the risk of restenosis after percutaneous coronary intervention have been reported.22 Moreover, recent studies have shown a strong correlation between higher IL-18 plasma levels and restenosis after percutaneous coronary intervention23 or clinical outcome in patients with coronary artery disease.24 Experimental animal models of other vascular injuries also demonstrated the critical role of IL-1β and IL-18 in neointimal formation. Isoda et al2 reported that neointimal formation is attenuated by the inhibition of the IL-1 signaling pathway in a murine model of perivascular cuff-induced vascular injury. Maffia et al3 also showed that IL-18 expression was increased in carotid arteries after balloon injury in rats and that neutralization of IL-18 inhibited neointimal formation. Thus, these results indicate that IL-1β and IL-18 act as important mediators for the development of atherosclerosis and restenosis. Interestingly, the recent AtheroGene study showed that plasma caspase-1 levels are predictive of future cardiovascular death in patients with coronary artery disease.25 Therefore, we postulated that ASC may regulate the expression of IL-1β and IL-18 via a caspase-1–dependent pathway in the vascular wall after vascular injury and modulate vascular inflammation and VSMC proliferation.
It is also noted that ASC deficiency had no effect on apoptosis after vascular injury. Although it has recently been accepted that ASC regulates the process of apoptosis, its precise mechanisms are unknown. Evidence from overexpression studies indicates that ASC can promote apoptosis in a Bax- and caspase-9–dependent manner,20,26 and antisense-mediated knockdown of ASC protects the cells from apoptosis induced by cytotoxic agents.7 ASC also has been implicated in the apoptotic process induced by the death receptor signaling pathway.19 Although we observed no significant difference in vascular wall apoptosis in response to injury between wild-type and ASC–/– mice, further investigations are required to elucidate the role of ASC in apoptosis after injury.
Increasing evidence indicates the importance of vascular progenitor cells derived from bone marrow in vascular development and remodeling. In particular, we and other investigators have shown that reendothelialization (eg, vascular repair) by bone marrow–derived endothelial progenitor cells is one of the important determinant factors for neointimal formation after vascular injury.12,27,28 In this study, however, ASC deficiency had no effect on reendothelialization at the early phase after vascular injury. Furthermore, ASC deficiency did not influence the number of endothelial progenitor cells in the peripheral circulation; this suggests that inhibition of neointimal formation in ASC–/– mice may be mediated through mechanisms different from those of vascular repair by reendothelialization. Furthermore, it is unlikely that reendothelialization after vascular injury is influenced by the ASC-regulated inflammatory cytokines IL-1β and IL-18.
We demonstrated that ASC deficiency in bone marrow cells reduced neointimal formation after vascular injury. Recent investigations have shown that bone marrow cells participate in neointimal formation after vascular injury29; however, the role of bone marrow cells is not yet fully understood. ASC has been shown to regulate caspase-1–mediated IL-1β and IL-18 production.9,10 Furthermore, ASC is reported to possess the potential to modulate nuclear factor-
B activation.30 Therefore, ASC may regulate inflammatory cytokine production through caspase-1–dependent and –independent ways. Interestingly, ASC-deficient VSMCs did not display any overt defects in proliferation activity and mitogen-activated protein kinase activation. These data are consistent with the results of BMT experiments that neointimal formation was not effectively reduced in ASC–/– mice in which bone marrow was replaced with wild-type bone marrow cells. Taken together, these results suggest a critical role of bone marrow–derived ASC in neointimal formation after vascular injury.
In the present study, we used a wire-mediated vascular injury model because it allows us to reproduce complete endothelial cell denudation and neointimal formation after injury.11,12 This model induces robust neointimal formation at 21 days after injury even in the control mice. Although the contribution of bone marrow cells to neointimal formation is controversial, Tanaka et al29 reported that wire-mediated vascular injury is suitable for investigating the role of bone marrow cells in vascular remodeling after injury. We also detected the bone marrow–derived -SMA–positive cells in the neointima. Furthermore, there are some reports in the literature describing that bone marrow–derived cells potentially participate in the lesion formation after injury.31–34 Recently, Yamada et al32 demonstrated that bone marrow–derived -SMA–positive cells did not express SM1 (a marker for relatively mature VSMCs), suggesting that these cells in the neointima have a relatively immature phenotype.
The present study has several limitations. First, the model used is not a reliable experimental model of human angioplasty because the injury was produced on a normal nonatheromatous artery. Second, the femoral artery is not similar to other arteries (eg, coronary artery) with respect to its response to vascular injury. Therefore, further investigations are required to elucidate the precise role of ASC in the development of atherosclerosis and restenosis.
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Conclusions |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionConclusionsReferences |
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We clearly demonstrated that ASC deficiency reduced neointimal formation after vascular injury. In particular, the absence of ASC in bone marrow cells plays a critical role in the attenuation of the progression of neointimal formation. Our data suggest that bone marrow–derived ASC is essential for the development of atherosclerosis and restenosis after percutaneous coronary intervention and identify ASC as a novel therapeutic target for cardiovascular diseases.
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Acknowledgments |
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We thank Junko Nakayama, Tomoko Hamaji, and Kazuko Misawa for excellent technical assistance.
Sources of Funding
This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology (to Dr M. Takahashi); the Ministry of Health, Labor and Welfare (to Drs M. Takahashi and Ikeda); and a Grant-in-Aid for Scientific Research (C-18590524 to Dr Masumoto) from the Japanese Society for the Promotion of Science.
Disclosures
None.
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Footnotes |
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*The first 2 authors contributed equally to this work.
The online Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.107.746453/DC1.
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Circulation 2008 117: 3055-3056.
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