Published online before print May 1, 2008, doi: 10.1161/CIRCRESAHA.108.173682
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© 2008 American Heart Association, Inc.
Molecular Medicine |
Adventitial Mast Cells Contribute to Pathogenesis in the Progression of Abdominal Aortic Aneurysm
From the Department of Internal Medicine (T.T., T.I., T.E., K. Kitamura), Circulatory and Body Fluid Regulation, Faculty of Medicine; Frontier Science Research Center (J.K.), Department of Pathology (K.H., Y.A.), Department of Cardiovascular, Thoracic and General Surgery (K. Kojima, M.Y., Y.Y., K.N., T.O.), and Department of Parasitology (F.N.-U., Y.N.), Faculty of Medicine, University of Miyazaki; and Research Institute (Y.M.), Saitama Cancer Center, Saitama, Japan.
Correspondence to Toshihiro Tsuruda, MD, PhD, Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan. E-mail ttsuruda{at}med.miyazaki-u.ac.jp
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Abstract |
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Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (+/+) rats following periaortic application of calcium chloride (CaCl2) treatment but not in the mast cell–deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E–deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA.
Key Words: adventitia • inflammation • mast cell • matrix metalloproteinase • aneurysm
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Abdominal aortic aneurysm (AAA), a relatively common disorder among elderly people, is pathologically characterized by atherosclerosis of the intima and disruption or attenuation of the elastic media with various degrees of adventitial inflammatory infiltration.1,2 Because approximately 4% of adults older than 65 years harbor AAA, it is among the leading 15 causes of death in elderly persons in the United States.3 Although substantial efforts have been made to clarify the mechanism of development of AAA, there is currently no effective method to inhibit enlargement of AAA. Repair surgery is necessary to prevent rupture in patients with progressively enlarging AAA, whereas the operative risk is often relatively high because of the other complications resulting from aging.
Recent reports suggest that chronic inflammation of the aortic wall and progressive degradation of extracellular matrix proteins are involved in the development, progression, or rupture of AAA.2,4–8 As a component of the immune system, mast cells play a critical role in defending hosts against pathogens by releasing a number of immunoregulatory mediators.9 These cells have also been shown to initiate the inflammatory response by releasing proinflammatory cytokines, growth factors, angiogenic mediators, and proteases,10 as well as by recruiting other inflammatory cells, such as neutrophils, macrophages, and T lymphocytes.11–13 Mast cells are present in the outer media or adventitia of the atherosclerotic aorta,14 where enzymes in the mast cell granules are assumed to induce apoptosis in vascular smooth muscle cells and to activate matrix metalloproteinases (MMPs).15,16
Based on these findings, we hypothesized that adventitial mast cells play a pivotal role in aortic aneurysmal dilatation by destroying medial elastic tissue and by inducing the adventitial inflammation. The present study was conducted first to characterize mast cell infiltrates in human AAA tissues and then extended to clarify the role of this type of immune cell in AAA development with rodent models of AAA and with cultured mast cells.
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Materials and Methods |
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An expanded Materials and Methods section is available in the online data supplement at http://circres.ahajournal.org. This study was approved by the Human Investigation Review Committee of the University of Miyazaki (No. 99) and conformed with the principles outlined in the Declaration of Helsinki (Cardiovasc Res. 1997;35:2–4). The animal study was performed in accordance with the Animal Welfare Act and with approval of the University of Miyazaki Institutional Animal Care and Use Committee (2004-096-4). This investigation also conformed with the Guide for the Care and Use of Laboratory Animals (NIH Publication No. 85-23, revised 1996).
Statistical Analysis
All data were analyzed with SPSS software version 11.0 (SPSS Inc). Differences between 2 groups were analyzed by Student’s t test, and those between aortic diameters before and after periaortic application of CaCl2 were analyzed by paired t test. Multiple comparisons were done with the 
2 test or 1-way ANOVA, followed by Scheffè’s test, and the Pearson’s correlation coefficient test was used to assess the relationship between the diameter and cell density. To accurately analyze zymogram and Western blot, standard curves were made by serial dilution of the samples, and the bands on gels were quantified based on the optical densities. The data are expressed as the means±SEM or as the median with the 10% to 90% range and outlying value. Statistical significance was accepted at P<0.05.
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Results |
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Patient Characteristics
Table I in the online data supplement shows the basal clinical parameters of the patients enrolled in this study. Both the AAA patients and those with advanced atherosclerosis were significantly (P<0.01) older than the control patients, but no difference was noted between the AAA and advanced atherosclerosis groups. The AAA group showed significantly higher rates of hypertension and cigarette smoking, but a lower rate of diabetes mellitus, compared with the advanced atherosclerosis group.
Mast Cell Density in Aortas With or Without AAA
Figure 1A illustrates the mast cell numbers positive for tryptase, a major neutral protease of mast cell secretory granules, in the controls, atherosclerotic aortas, and AAA tissues. The number of mast cells in the advance atherosclerotic aorta increased (P<0.05) as compared with the control, and a further increase (P<0.01) was observed in the AAA tissue, showing a positive correlation between the cell number and the maximal diameter of aneurysm (Figure 1B). Moreover, degranulated mast cells were rarely seen in the control and atherosclerotic aorta; however, the ratio of degranulated mast cells to the total mast cell number in AAA was significantly (P<0.01) higher than in the other groups (Figure 1C). Meanwhile, no significant difference was noted in the number of macrophages positive for CD68 among the groups (Figure 1D).
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Protein Expressions and Gelatinase Abundance in Human AAA
The protein expressions of tryptase, stem cell factor (SCF), a ligand for the protooncogene c-kit involved in maturation and differentiation of mast cells, and phosphorylation of c-kit were significantly (P<0.01) increased in the AAA tissues compared with control or atherosclerotic aorta without dilatation (Figure 2A and 2B). In the serial sections, the immunoreactivity for SCF was specifically localized in the cytoplasm of mast cells positive for tryptase in the adventitia of AAA specimens (Figure 2C through 2E). The zymographic gelatinase abundance corresponding to both forms of latent and active MMP-9 (P<0.01) and the ratio of active/latent zymographic MMP-2 (P<0.05) abundance were significantly increased in the AAA tissues (Figure 2A and 2B). As shown in Figure 3A and 3B, the immunoreactivity of MMP-9 was similarly distributed in the plaque area of advanced atherosclerotic aorta and AAA, although it significantly increased in the outer media and adventitia of AAA. Figure 3C shows that gelatinolytic activity corresponding to MMP-9 was distributed in the outer media or adventitia of AAA. The region where gelatinolysis occurred was observed as white or pale pink, whereas other areas with no gelatinolysis were red (Figure 3Ca and 3Cb). The specificity of this gelatinolysis was confirmed by the inhibition by the broad MMP inhibitor, 1,10-phenanthroline (Figure 3Cc and 3Cd). The MMP-9 immunoreactivity was mainly (>98%) colocalized with macrophages and some (<2%) with T lymphocytes, whereas there was no colocalization with mast cells or smooth muscle cells (supplemental Figure I).
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Aneurysm Induction in Control and Mast Cell–Deficient Ws/Ws Rats
Figure 4A shows the representative immunohistological pictures of abdominal aortas of the control (+/+) rats and those of mast cell–deficient Ws/Ws at 14 days after the periaortic application of calcium chloride (CaCl2). Figure 4B illustrate that the periaortic application of CaCl2 led to destruction of the architecture of aortic walls, increasing aortic diameter by up to 55% in the control (+/+) rats at day 14 as compared with that before the CaCl2 application, whereas the aorta of the Ws/Ws rats was found to be resistant to CaCl2, showing only a 13% increase at day 14. The time-dependent aortic dilatation was accompanied with progressive adventitial inflammation characterized by infiltrations of mast cells and T lymphocytes and by increased rate of degranulated mast cells and numbers of microvessels in the control (+/+) rats, but such changes were smaller in the Ws/Ws rats. In addition, the elastin areas of the aortic media were time-dependently reduced in the control (+/+) rats but not in the Ws/Ws rats. Zymographic gelatinase abundance of total MMP-2 of aortic tissue of the Ws/Ws rats was significantly less at day 7, and those of MMP-9 were so at days 7 and 14, compared with the control (+/+) rats. Meanwhile, no changes were noted in the number of macrophages between the control (+/+) and Ws/Ws rats with AAA induction. Furthermore, blood pressure measured with the tail-cuff method, and the number of neutrophils and apoptotic cells showed no difference between the 2 groups of rats with AAA induction (data not shown).
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Effects of Tranilast on Aneurysm Formation of Control Rats
Figure 5A and 5B illustrates the effect of tranilast [N-(3,4-dimethoxycinnnamoyl) anthranilic acid] on the morphological changes in the CaCl2-induced aneurysm formation of the control (+/+) rats. The administration of tranilast significantly attenuated the dilatation of aorta, the inflammatory infiltrations of mast cells and T lymphocytes, and the microvessel formation in the adventitia of the aortas treated with CaCl2. In addition, elastin area was preserved in aortas of the treated group. Figure 5C shows that zymographic abundance of total MMP-2 in aortic tissue was slightly reduced following treatment with tranilast, and a significant reduction (P<0.01) was noted in that of MMP-9. Meanwhile, no significant changes were found in the number of macrophages or the proportion of degranulated mast cells between 2 groups with or without the tranilast treatment. Furthermore, the number of neutrophils and apoptotic cells was not altered significantly between the groups (data not shown).
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Mast Cell Activation in Apolipoprotein E–Deficient Mouse Model of AAA
Figure 6A and 6C illustrates the representative pictures and quantitative evaluations of abdominal aortas of the control and those infused with angiotensin (Ang) II subcutaneously for 28 days treated without or with tranilast in the spontaneously apolipoprotein (apo)E-deficient mice. The Ang II–induced increases in the size of aorta and plaque area were significantly (P<0.05) attenuated by the tranilast treatment. Figure 6B and 6C shows the other representative pictures and quantitative evaluations of elastin formation, distribution of mast cells, T lymphocytes, macrophages, and microvessels in the apoE-deficient mice infused with Ang II. The enlarged abdominal aorta was accompanied by increasing the number of mast cells, T lymphocytes, and capillary vessels, as well as the proportion of degranulated mast cells in the adventitia, whereas these were significantly reduced following the tranilast treatment. In addition, a significant reduction of elastin area in aortas of these mice was preserved with the treatment (P<0.01). As shown in Figure 6D, zymographic abundance of latent form MMP-9 in the aortic tissues of apoE-deficient mice infused with Ang II was significantly (P<0.05) reduced by the tranilast treatment. However, the number of macrophages or the magnitude of zymographic MMP-2 abundance was not altered significantly by the tranilast treatment. Furthermore, the number of neutrophils or apoptotic cells was not changed significantly by the treatment (data not shown).
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Zymographic MMP-9 Abundance of Cultured Mast Cells and Monocyte/Macrophage
The latent form of zymographic MMP-9 abundance in the culture media significantly (P<0.01) increased following coculture of activated HMC-1 and U937 cells when compared with that from control HMC-1, activated HMC-1, or U937 cultured alone (Figure 7A). Figure 7B shows the effect of tranilast on MMP-9 abundance produced from coculture of activated HMC-1 and U937 cells: 100 and 300 µmol/L tranilast significantly (P<0.01) decreased the zymographic MMP-9 abundance in the conditioned media. Next, we examined whether tranilast reduced MMP-9 abundance by acting on HMC-1 cells or on U937 cells. As shown in Figure 7C, tranilast had no direct effect on MMP-9 abundance produced from U937 incubated with conditioned media of activated HMC-1; however, it reduced MMP-9 abundance (P<0.01) when U937 cells were cultured with the conditioned media of activated HMC-1 cells that had been pretreated with tranilast. Similar increase in MMP-9 abundance (P<0.01) was observed when U937 cells were incubated alone with conditioned media of activated HMC-1, but this increase was attenuated (P<0.05) in the conditioned media of HMC-1 cells that had been pretreated with 50 µg/mL monoclonal interferon (IFN)-
antibody (Figure 8A). Figure 8B shows IFN- secretion from cultured U937 cells and control or activated HMC-1 cells. The IFN- secretion from HMC-1 cells significantly (P<0.05) increased on activation, but that from U937 was minimal. Meanwhile, the IFN- secretion from activated HMC-1 cells was significantly (P<0.05) decreased by 300 µmol/L tranilast (Figure 8C).
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As shown in supplemental Figure IIA through IID, coculture of primary murine bone marrow–derived mast cells (BMMCs) and peritoneal macrophages also significantly (P<0.05) increased the MMP-9 abundance, compared to that from BMMCs, activated BMMCs or peritoneal macrophages, whereas it was significantly (P<0.01) inhibited by 100 and 300 µmol/L tranilast. Meanwhile, the conditioned media obtained from the activated BMMCs did not alter the MMP-9 abundance in culture media of peritoneal macrophages. The IFN- secretion from BMMCs did not increase on the activation, whereas the coculture of activated BMMCs and peritoneal macrophages stimulated to increase it, compared to that from peritoneal macrophage cultured alone.
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Discussion |
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Carrying out the present study with human samples of AAA, we observed several findings that imply a role of mast cells in development or progression of AAA. First, mast cell numbers increased in the aortic adventitia and outer media with the advanced stage of atherosclerosis, but a further increase was observed in AAA, with the significant correlation between the cell number and the maximal diameter of AAA. More importantly, the proportion of degranulated mast cells was significantly higher in AAA than in controls and atherosclerotic aortas. In autopsy cases, mast cell number increased 2- to 4-fold at the aneurysmal sites of nonruptured or ruptured AAA as compared with the nondilated part of the aortas of those patients (supplemental Table II). Second, expression of tryptase and SCF, specifically localized in mast cells, and phosphorylation of c-kit (receptor for SCF) were increased in the AAA tissues compared with the controls or atherosclerotic aortas. Thus, accumulation or activation of mast cells in the outer media and adventitia appears involved in the development, progression, or rupture of AAA.
To further clarify the role of adventitial mast cells in development of AAA, we examined whether or not aneurysmal dilatation of the abdominal aortas occurred following periaortic application of CaCl2 in mutant mast cell–deficient Ws/Ws and control (+/+) rats.17,18 The progressive dilatation of abdominal aortas, accompanied by mast cell accumulation and degranulation, occurred in the control (+/+) rats, but such dilatation was not observed in the Ws/Ws rats. In addition, spontaneously hyperlipidemic apoE-deficient mice19,20 exhibited the mast cell accumulation and activation at the aneurysmal site of abdominal aortas. Whereas, tranilast, an inhibitor of mast cell degranulation, effectively suppressed the progression of these experimental models of AAA. Collectively, our present data support the recent studies21–23 and extend our understanding of the important role for adventitial mast cells in the development of AAA.
Chronic inflammation in the aortic wall, particularly in the adventitia, is assumed to have a detrimental role in AAA.5–8,24 Mast cells serve as an important source of proinflammatory mediators and cytokines that can activate T lymphocytes25 and macrophages,26 whereas mast cells become activated on direct contact with T lymphocytes.27 Accordant with these reports, T lymphocytes were increased concord with mast cells in the rodent models of AAA. In addition to proinflammatory cytokines, a number of substances or enzymes produced from mast cells are assumed to be involved in the development of AAA. Mast cells produce tryptase or chymase, which degrades extracellular matrix by activating MMPs or induce apoptosis of vascular smooth muscle cells.15,16,28 Indeed, mast cells double positive for tryptase and chymase were predominately observed in the adventitia of human AAA (supplemental Figure III).
It is important to note that humans and rodents share the common pathological features, showing the unchanged number of macrophages between the dilated and nondilated aortas, irrespectively of the increasing number of mast cells and MMP-9 activity. Consistent with the previous report,29 MMP-9 activity was mainly distributed in macrophages at the outer media and adventitia of human AAA, suggesting a possible crosstalk between mast cells and macrophages to produce MMP-9. Smoking is a risk factor for AAA,30 and the rate of cigarette smoking was substantially high in AAA patients in this study. Smoking is proposed to promote pathogenesis of AAA through the 5-lipooxygenase pathway,31,32 and mast cells are reported to be critical to cause an increase the enzyme in macrophages.26 Keeping this mind is also important that the mast cells coculturing with the monocyte/macrophage augmented zymographic activity of MMP-9. Our finding in vitro suggests an important contribution for mast cells to augment MMP-9 secretion (latent form) in macrophages by either direct cell-to-cell contact or through humoral mediators such as IFN-,7,22 and it is thereby further activated in the extracellular compartment in vivo. On the other hand, coculturing of mast cells with the adventitial fibroblasts isolated from human AAA did not alter the zymographic MMPs-2 and -9 abundance (data not shown).
Other characteristic features of human AAA are angiogenesis33 and apoptosis of smooth muscle cells.34 A number of biological active substances contained in mast cell granules and the activation of the MMP-9 coincides with angiogenic process.35 Consistent with this notion,6,36 the experimental models of AAA were accompanied by augmented angiogenesis in the aorta, but these changes were reduced by the tranilast. On the other hand, this study indicates the apoptosis might play a minor role in the mechanism. Taken together, this study suggests that mast cells contribute to the pathogenesis of AAA by activating MMP-9 and angiogenesis with the other inflammatory cells in the adventitia of aortic wall.
Lastly, we should mention limitations of the present study. First, the phenotype of Ws/Ws rats is not specific to mast cell deletion but also shows hypopigmentation of the skin and hypoplastic anemia at an early age.37 Because mast cells were not reconstituted to the aortas of Ws/Ws rats, we could not verify the roles of mast cells by their reconstitution. The second, tranilast, was initially identified as an inhibitor of mast cell degranulation.38,39 However, this compound has been shown the antiproliferative and antiinflammatory actions in other cell types, such as vascular smooth muscle cells and neutrophils.40,41 We demonstrated the specific action of tranilast on mast cells but not macrophages in vitro; however, we cannot deny the possibility that this compound would affect the other vascular components. In this study, tranilast inhibited the accumulation of mast cells in both experimental models of AAA but did not change the proportion of the cells degranulated in the rat model. Transforming growth factor-β is reported to be increased in human AAA42 and is also an important chemotaxin for recruiting the mast cells.43 Although the inhibition of mast cell degranulation by the tranilast may likely depend on species specific or temporal during the aneurysmal formation, we postulate that tranilast may have a potential to attenuate the aneurysmal formation by inhibiting the migration of mast cells through transforming growth factor-β signaling,44 as well as by attenuating the activation of the cells (supplemental Figure IV). Further studies would be aimed to explore the detailed mechanisms by which tranilast prevent AAA, but this study illustrates the feasibility for tranilast as a therapeutic tool in preventing AAA from enlarging.
In summary, this study provides the evidence for the involvement of adventitial mast cells in concert with other inflammatory cells in AAA development, offering a novel therapeutic strategy of pharmacologically suppressing mast cell activity in treating patients with AAA.
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Acknowledgments |
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We are greatly indebted to Dr Akira Ishihara (Prefectural Nobeoka Hospital, Miyazaki, Japan) for preparation of ruptured aneurysmal tissues and to Ritsuko Sotomura and Yoko Sekita for expert technical assistance.
Sources of Funding
This study was supported by grants-in-aid from the 21st Century Centers of Excellence Program (Life Science) and Scientific Research from the Ministry of Education, Culture, Sport, Science and Technology, Japan; grants-in-aid from the Suzuken Memorial Foundation; the Mochida Memorial Foundation for Medical and Pharmaceutical Research; and a Kimura Memorial Heart Foundation research grant.
Disclosures
None.
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Footnotes |
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Original received May 10, 2007; first resubmission received September 12, 2007; second resubmission received February 12, 2008; revised second resubmission received April 21, 2008; accepted April 23, 2008.
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