Faculty Profiles - OGATA Aika

Administration of an antibody against apoptosis inhibitor of macrophage prevents aortic aneurysm progression in mice. Invited Reviewed

Fujii T, Yamawaki-Ogata A, Terazawa S, Narita Y, Mutsuga M

Scientific reports Vol. 14 ( 1 ) page： 15878 2024.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Apoptosis inhibitor of macrophage (AIM) is known to induce apoptosis resistance in macrophages and to exacerbate chronic inflammation, leading to arteriosclerosis. The role of AIM in aortic aneurysm (AA) remains unknown. This study examined the effects of an anti-AIM antibody in preventing AA formation and progression. In apolipoprotein E-deficient mice, AA was induced by subcutaneous angiotensin II infusion. Mice were randomly divided into two groups: (i) AIM group; weekly anti-murine AIM monoclonal antibody injection (n = 10), and (ii) IgG group; anti-murine IgG antibody injection as control (n = 14). The AIM group, compared with the IgG group, exhibited reduced AA enlargement (aortic diameter at 4 weeks: 2.1 vs. 2.7 mm, respectively, p = 0.012); decreased loss of elastic lamellae construction; reduced expression levels of IL-6, TNF-α, and MCP-1; decreased numbers of AIM-positive cells and inflammatory M1 macrophages (AIM: 1.4 vs. 8.0%, respectively, p = 0.004; M1 macrophages: 24.5 vs. 55.7%, respectively, p = 0.017); and higher expression of caspase-3 in the aortic wall (22.8 vs. 10.5%, respectively, p = 0.019). Our results suggest that administration of an anti-AIM antibody mitigated AA progression by alleviating inflammation and promoting M1 macrophage apoptosis.

DOI： 10.1038/s41598-024-66791-7

Development of novel waxy bone haemostatic agents composed of biodegradable polymers with osteogenic-enhancing peptides in rabbit models Invited Reviewed

Tsukasa Ohno, Hiroto Suenaga, Aika Yamawaki-Ogata, Kei Kanie, Ryuji Kato, Koichiro Uto, Mitsuhiro Ebara, Hideki Ito, Yuji Narita, Akihiko Usui, Masato Mutsuga

Interdisciplinary CardioVascular and Thoracic Surgery Vol. 37 ( 5 ) 2023.11

Language：English Publishing type：Research paper (scientific journal)

<jats:title>Abstract</jats:title>
<jats:p />
<jats:sec>
<jats:title>OBJECTIVES</jats:title>
<jats:p>The use of bone wax (BW) is controversial for sternal haemostasis because it increases the risk of wound infection and inhibits bone healing. We developed new waxy bone haemostatic agents made from biodegradable polymers containing peptides and evaluated them using rabbit models.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>METHODS</jats:title>
<jats:p>We designed 2 types of waxy bone haemostatic agents: peptide wax (PW) and non-peptide wax (NPW), which used poly(ε-caprolactone)-based biodegradable polymers with or without an osteogenesis-enhancing peptide, respectively. Rabbits were randomly divided into 4 groups based on treatment with BW, NPW, PW or no treatment. In a tibial defect model, the bleeding amount was measured and bone healing was evaluated by micro-computed tomography over 16 weeks. Bone healing in a median sternotomy model was assessed for 2 weeks using X-ray, micro-computed tomography, histological examination and flexural strength testing.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>RESULTS</jats:title>
<jats:p>The textures of PW and NPW (n = 12 each) were similar to that of BW and achieved a comparable degree of haemostasis. The crevice area of the sternal fracture line in the BW group was significantly larger than that in other groups (n = 10 each). The PW group demonstrated the strongest sternal flexural strength (n = 10), with complete tibial healing at 16 weeks. No groups exhibited wound infection, including osteomyelitis.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>CONCLUSIONS</jats:title>
<jats:p>Waxy biodegradable haemostatic agents showed satisfactory results in haemostasis and bone healing in rabbit models and may be an effective alternative to BW.</jats:p>
</jats:sec>

DOI： 10.1093/icvts/ivad170

Fabrication of pH-responsive poly(vinyl alcohol)-based microfibers crosslinked with copolymers containing benzoxaborole and carboxy groups Invited Reviewed

Momose, T; Takeuchi, K; Uchida, H; Saito, S; Nakada, K; Mutsuga, M; Yamawaki-Ogata, A; Narita, Y; Kotsuchibashi, Y

POLYMER Vol. 283 2023.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Polymer

Water-insoluble pH-responsive poly (vinyl alcohol) (PVA)-based microfibers were prepared using terpolymer of poly ([2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC)-co-methacrylic acid (MAAc)-co-5-methacrylamido-1,2-benzoxaborole (MAAmBO)) (TP) containing a quaternary ammonium cation, as well as carboxy and benzoxaborole groups. The surface of the microfibers could be positively charged by the permanent positive charge of the METAC units owing to the presence of the quaternary ammonium cation. The MAAc units formed a covalent bond with the hydroxy group of the vinyl alcohol unit by thermal treatment at 135 °C for 24 h, and the MAAmBO units formed a dynamic covalent bond with the diol group in PVA. After thermal crosslinking for 24 h, the PVA/TP microfibers exhibited almost 100% of the residual weight after immersion in water at 80 °C for 30 min. The diameters of the dried PVA/TP_25 wt% fibers were 21.4 ± 3.9 μm, and the swelling ratio was 1.65 ± 0.16 after immersing in water for 24 h. All microfibers showed a low degree of hemolysis (<5%). The PVA/TP_25 wt% fibers were strongly dyed with anionic acid red 1 (AR1) molecules at pH 3 and with cationic methylene blue (MB) molecules at pH 12, since the balance of the surface charge depend on the solution pH. These microfibers could be bundled and twisted to improve their mechanical properties; the required fracture energy after twisting was 2.30 ± 0.91 times higher than that before twisting.

DOI： 10.1016/j.polymer.2023.126236

A review of current status of cell-based therapies for aortic aneurysms. Invited Reviewed

Yamawaki-Ogata A, Mutsuga M, Narita Y

Inflammation and regeneration Vol. 43 ( 1 ) page： 40 2023.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Inflammation and Regeneration

An aortic aneurysm (AA) is defined as focal aortic dilation that occurs mainly with older age and with chronic inflammation associated with atherosclerosis. The aneurysmal wall is a complex inflammatory environment characterized by endothelial dysfunction, macrophage activation, vascular smooth muscle cell (VSMC) apoptosis, and the production of proinflammatory molecules and matrix metalloproteases (MMPs) secreted by infiltrated inflammatory cells such as macrophages, T and B cells, dendritic cells, neutrophils, mast cells, and natural killer cells. To date, a considerable number of studies have been conducted on stem cell research, and growing evidence indicates that inflammation and tissue repair can be controlled through the functions of stem/progenitor cells. This review summarizes current cell-based therapies for AA, involving mesenchymal stem cells, VSMCs, multilineage-differentiating stress-enduring cells, and anti-inflammatory M2 macrophages. These cells produce beneficial outcomes in AA treatment by modulating the inflammatory environment, including decreasing the activity of proinflammatory molecules and MMPs, increasing anti-inflammatory molecules, modulating VSMC phenotypes, and preserving elastin. This article also describes detailed studies on pathophysiological mechanisms and the current progress of clinical trials.

DOI： 10.1186/s41232-023-00280-8

Development of tissue adhesion barrier sheet functionalized with cell-selective adhesion peptides Invited Reviewed

Sugiyama, A; Kanie, K; Uto, K; Ebara, M; Ogata, A; Narita, Y; Kato, R

TISSUE ENGINEERING PART A Vol. 29 ( 13-14 ) 2023.7

Combinatorial analysis of tag peptides for enhancement of cell-adhesion short peptides Invited Reviewed

Fujimoto, A; Kanie, K; Ogata, A; Narita, Y; Kato, R

TISSUE ENGINEERING PART A Vol. 29 ( 13-14 ) 2023.7

Novel Functional Peptide for Next-Generation Vital Pulp Therapy Invited Reviewed

M. Watanabe, M. Okamoto, S. Komichi, H. Huang, S. Matsumoto, K. Moriyama, J. Ohshima, S. Abe, M. Morita, M. Ali, K. Takebe, I. Kozaki, A. Fujimoto, K. Kanie, R. Kato, K. Uto, M. Ebara, A. Yamawaki-Ogata, Y. Narita, Y. Takahashi, M. Hayashi

Journal of Dental Research Vol. 102 ( 3 ) page： 322 - 330 2023.3

Language：English Publishing type：Research paper (scientific journal)

Although vital pulp therapy should be performed by promoting the wound-healing capacity of dental pulp, existing pulp-capping materials were not developed with a focus on the pulpal repair process. In previous investigations of wound healing in dental pulp, we found that organic dentin matrix components (DMCs) were degraded by matrix metalloproteinase-20, and DMC degradation products containing protein S100A7 (S100A7) and protein S100A8 (S100A8) promoted the pulpal wound-healing process. However, the direct use of recombinant proteins as pulp-capping materials may cause clinical problems or lead to high medical costs. Thus, we hypothesized that functional peptides derived from recombinant proteins could solve the problems associated with direct use of such proteins. In this study, we identified functional peptides derived from the protein S100 family and investigated their effects on dental pulp tissue. We first performed amino acid sequence alignments of protein S100 family members from several mammalian sources, then identified candidate peptides. Next, we used a peptide array method that involved human dental pulp stem cells (hDPSCs) to evaluate the mineralization-inducing ability of each peptide. Our results supported the selection of 4 candidate functional peptides derived from proteins S100A8 and S100A9. Direct pulp-capping experiments in a rat model demonstrated that 1 S100A8-derived peptide induced greater tertiary dentin formation compared with the other peptides. To investigate the mechanism underlying this induction effect, we performed liquid chromatography–tandem mass spectrometry analysis using hDPSCs and the S100A8-derived peptide; the results suggested that this peptide promotes tertiary dentin formation by inhibiting inflammatory responses. In addition, this peptide was located in a hairpin region on the surface of S100A8 and could function by direct interaction with other molecules. In summary, this study demonstrated that a S100A8-derived functional peptide promoted wound healing in dental pulp; our findings provide insights for the development of next-generation biological vital pulp therapies.

DOI： 10.1177/00220345221135766

Administration of anti-inflammatory M2 macrophages suppresses progression of angiotensin II-induced aortic aneurysm in mice. Reviewed

Ashida S, Yamawaki-Ogata A, Tokoro M, Mutsuga M, Usui A, Narita Y

Scientific reports Vol. 13 ( 1 ) page： 1380 2023.1

Bi-layered carboxymethyl cellulose-collagen vitrigel dual-surface adhesion-prevention membrane Invited Reviewed

Yue Wang, Kei Kanie, Toshiaki Takezawa, Miki Horikawa, Kyoshiro Kaneko, Ayako Sugimoto, Aika Yamawaki-Ogata, Yuji Narita, Ryuji Kato

CARBOHYDRATE POLYMERS Vol. 285 page： 119223 2022.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

During wound regeneration, both cell adhesion and adhesion-inhibitory functions must be controlled in parallel. We developed a membrane with dual surfaces by merging the properties of carboxymethyl cellulose (CMC) and collagen using vitrification. A rigid membrane was formed by vitrification of a bi-layered CMC and collagen hydrogel without using cross-linking reagents, thus providing dual functions, strong cell adhesion-inhibition with the CMC layer, and cell adhesion with the collagen layer. We referred to this bi-layered CMC-collagen vitrigel membrane as "Bi-C-CVM" and optimized the process and materials. The introduction of the CMC layer conferred a "tough but stably wet" property to Bi-C-CVM. This enables Bi-C-CVM to cover wet tissue and make the membrane non-detachable while preventing tissue adhesion on the other side. The bi-layered vitrification procedure can expand the customizability of collagen vitrigel devices for wider medical applications.

DOI： 10.1016/j.carbpol.2022.119223

Alternative therapeutic strategy for existing aortic aneurysms using mesenchymal stem cell-derived exosomes. Invited Reviewed

Kozakai M, Narita Y, Yamawaki-Ogata A, Fujimoto KL, Mutsuga M, Tokuda Y, Usui A

Expert opinion on biological therapy Vol. 22 ( 1 ) page： 95 - 104 2022.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Expert Opinion on Biological Therapy

Background: Several studies demonstrated the therapeutic potential of mesenchymal stem cell–derived exosomes (MSC-exs) based on their anti-inflammatory properties. The objective was to determine the therapeutic effects of MSC-exs on aortic aneurysms (AAs) caused by atherosclerosis. Research design and methods: Apolipoprotein E knockout mice with AAs induced by angiotensin II were injected with MSC-exs or saline as a control. The change in the diameter of the aorta was measured. The expression of AA-related proteins and the histology of the aortic wall were investigated at 1 week after treatment. MicroRNA and protein profiles of MSC-exs were examined. Results: MSC-exs significantly attenuated AA progression (2.04 ± 0.20 mm in the saline group and 1.34 ± 0.13 mm in the MSC-ex group, P = 0.004). In the MSC-ex group, the expression of IL-1β, TNF-α and MCP-1 decreased, and expression of IGF-1 and TIMP-2 increased. MSC-ex induced the M2 phenotype in macrophages and suppressed the destruction of the elastic lamellae in the aortic wall. MSC-exs contained high levels of 10 microRNAs that inhibit AA formation and 13 proteins that inhibit inflammation and promote extracellular matrix synthesis. Conclusions: MSC-ex might be a novel alternative therapeutic tool for treatment of existing AAs.

DOI： 10.1080/14712598.2022.2005575

Fabrication of Cationic Poly(vinyl alcohol) Films Cross-Linked Using Copolymers Containing Quaternary Ammonium Cations, Benzoxaborole, and Carboxy Groups. Invited Reviewed

Fujimoto K, Yamawaki-Ogata A, Narita Y, Kotsuchibashi Y

ACS omega Vol. 6 ( 27 ) page： 17531 - 17544 2021.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ACS Omega

Water-insoluble cationic poly(vinyl alcohol) (PVA) films were fabricated using a mixed aqueous solution of PVA and poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC)-co-methacrylic acid (MAAc)-co-5-methacrylamido-1,2-benzoxaborole (MAAmBO)) copolymer (3D). The surface of the PVA film is typically negatively charged, and simple fabrication methods for water-insoluble PVA films with cationic surface charges are required to expand their application fields. METAC, which has a permanent positive charge owing to the presence of a quaternary ammonium cation, was selected as the cationic unit. The MAAc and MAAmBO units were used as two types of cross-linking structures for the thermal cross-linking of the hydroxy and carboxy groups of the MAAc unit (covalent bonding) as well as the diol and benzoxaborole groups of the MAAmBO unit (dynamic covalent bonding). The films were thermally cross-linked at 135 °C for 4 h without the addition of materials. After immersion in surplus water at 80 °C for 3 h, the cross-linked PVA/3D films retained almost 100% of their weights. The ζ-potential of the water-insoluble PVA/3D film was 9.4 ± 0.8 mV. The PVA/3D film was strongly dyed using anionic acid red 1 (AR1) because of its positively charged surface. Interestingly, it could also be slightly dyed using cationic methylene blue (MB) and became transparent (original state) after immersion in water for 2 days. These results suggested that positive and negative charges coexisted in the PVA/3D film, and the surface properties were positively inclined. Moreover, the degree of hemolysis of the PVA/3D films was similar to that of the negative control, which showed high blood compatibility. To our knowledge, this is the first report on the fabrication of water-insoluble cationic PVA films using two types of cross-linking structures containing carboxy and benzoxaborole groups. The cross-linked PVA films were analyzed using Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and contact angle (CA) and ζ-potential measurement, as well as by determining the mechanical properties, adsorption of charged molecules, and biocompatibility. These readily fabricated water-insoluble PVA films with positive charges can show potential applications in sensors, adsorption systems, and antimicrobial materials.

DOI： 10.1021/acsomega.1c02013

Long term efficacy and fate of a right ventricular outflow tract replacement using an elastomeric cardiac patch consisting of caprolactone and D,L-lactide copolymers Invited Reviewed

Kazuro L. Fujimoto, Aika Yamawaki-Ogata, Koichiro Uto, Akihiko Usui, Yuji Narita, Mitsuhiro Ebara

Acta Biomaterialia Vol. 123 page： 222 - 229 2021.3

Language：English Publishing type：Research paper (scientific journal)

For decades, researchers have investigated the ideal material for clinical use in the cardiovascular field. Several substitute materials are used clinically, but each has drawbacks. Recently we developed biodegradable and elastic poly(ε-caprolactone-co-D,L-lactide) (P(CL-DLLA)) copolymers by adjusting the CL/DLLA composition, and evaluated the long-term efficacy and outcomes of these copolymers when used for right ventricular outflow tract (RVOT) replacement. This P(CL-DLLA) material was processed into a circular patch and used to replace a surgical defect in the RVOT of adult rats. Control rats were implanted with expanded polytetrafluoroethylene (ePTFE). Histologic evaluation was performed at 8, 24, and 48 weeks post-surgery. All animals survived the surgery with no aneurysm formation or thrombus. In all periods, ePTFE demonstrated fibrous tissue. In contrast, at 8 weeks P(CL-DLLA) showed infiltration of macrophages and fibroblast-like cells into the remaining material. At 24 weeks, P(CL-DLLA) was absorbed completely, and muscle-like tissue was present with positive staining for α-sarcomeric actinin and cardiac troponin T (cTnT). At 48 weeks, the cTnT-positive area had increased. The biodegradable and elastic P(CL-DLLA) induced cardiac regeneration throughout the 48-week study period. Future application of this material as a cardiovascular scaffold seems promising. Statement of significance: Biomaterials for reconstruction of tissue deficiencies in cardiovascular surgery require having suitable mechanical properties for cardiac tissue and biodegradation resulting in native tissue growth. Several biodegradable polymers such as poly-ε-caprolactone (PCL) and polylactic acid (PLA) have excellent biocompatibility and already been widely used clinically. In general, PCL and PLA are quite mechanically rigid. Meanwhile, significant elasticity is required in the high-pressure environment of the heart while the material is being replaced by new tissue. The present study provides a novel four-armed crosslinked poly(ε-caprolactone-co-D,L-lactide) (i.e., P(CL-DLLA)) material for cardiac patch, which was demonstrated properties including tissue-compatible, super-elastic nature, that made it suitable for long-term, in vivo RVOT repair. This super-elastic biomaterial could be useful for reconstruction of various muscular tissues deficiencies.

DOI： 10.1016/j.actbio.2021.01.022

Therapeutic effect of allogeneic bone marrow–derived mesenchymal stromal cells on aortic aneurysms Invited Reviewed

Naohiro Akita, Yuji Narita, Aika Yamawaki-Ogata, Akihiko Usui, Kimihiro Komori

Cell and Tissue Research Vol. 383 ( 2 ) page： 781 - 793 2021.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media Deutschland GmbH

We previously reported the effectiveness of autologous mesenchymal stromal cells (MSCs) for the treatment of aortic aneurysm (AA), mediated mainly by these cells’ anti-inflammatory properties. In this study, we investigate whether the therapeutic effects of allogeneic MSCs on AA are the same as those of autologous MSCs. To examine the immune response to allogeneic MSCs, C57BL/6 lymphocytes were co-cultured with BALB/c MSCs for 5 days in vitro. Apolipoprotein E-deficient C57BL/6 mice with AA induced by angiotensin II were randomly divided into three groups defined by the following intravenous injections: (i) 0.2 ml of saline (n = 10, group S) as a control, (ii) 1 × 106 autologous MSCs (isolated from C57BL/6, n = 10, group Au) and (iii) 1 × 106 allogeneic MSCs (isolated from BALB/c, n = 10, group Al). Two weeks after injection, aortic diameters were measured, along with enzymatic activities of MMP-2 and MMP-9 and cytokine concentrations in AAs. Neither allogenic (BALB/c) MSCs nor autologous (C57BL/6) MSCs accelerated the proliferation of lymphocytes obtained from C57BL/6. Compared with group S, groups Au and Al had significantly shorter aortic diameters (group S vs Au vs Al
2.29 vs 1.40 vs 1.36 mm, respectively, p &lt
0.01), reduced MMP-2 and MMP-9 activities, downregulated IL-6 and MCP-1 and upregulated expression of IGF-1 and TIMP-2. There were no differences in these results between groups Au and Al. Thus, our study suggests that treatment with allogeneic MSCs improves chronic inflammation and reduced aortic dilatation. These effects were equivalent to those of autologous MSCs in established mouse models of AA.

DOI： 10.1007/s00441-020-03295-6

Performance of a biodegradable composite with hydroxyapatite as a scaffold in pulp tissue repair Reviewed

Motoki Okamoto, Sayako Matsumoto, Ayato Sugiyama, Kei Kanie, Masakatsu Watanabe, Hailing Huang, Manahil Ali, Yuki Ito, Jiro Miura, Yujiro Hirose, Koichiro Uto, Mitsuhiro Ebara, Ryuji Kato, Aika Yamawaki-Ogata, Yuji Narita, Shigetada Kawabata, Yusuke Takahashi, Mikako Hayashi

Polymers Vol. 12 ( 4 ) page： 937 - 937 2020.4

Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Vital pulp therapy is an important endodontic treatment. Strategies using growth factors and biological molecules are effective in developing pulp capping materials based on wound healing by the dentin-pulp complex. Our group developed biodegradable viscoelastic polymer materials for tissue-engineered medical devices. The polymer contents help overcome the poor fracture toughness of hydroxyapatite (HAp)-facilitated osteogenic differentiation of pulp cells. However, the composition of this novel polymer remained unclear. This study evaluated a novel polymer composite, P(CL-co-DLLA) and HAp, as a direct pulp capping carrier for biological molecules. The biocompatibility of the novel polymer composite was evaluated by determining the cytotoxicity and proliferation of human dental stem cells in vitro. The novel polymer composite with BMP-2, which reportedly induced tertiary dentin, was tested as a direct pulp capping material in a rat model. Cytotoxicity and proliferation assays revealed that the biocompatibility of the novel polymer composite was similar to that of the control. The novel polymer composite with BMP-2-induced tertiary dentin, similar to hydraulic calcium-silicate cement, in the direct pulp capping model. The BMP-2 composite upregulated wound healing-related gene expression compared to the novel polymer composite alone. Therefore, we suggest that novel polymer composites could be effective carriers for pulp capping.

DOI： 10.3390/polym12040937

Hydrogen water alleviates obliterative airway disease in mice. Reviewed

Ozeki N, Yamawaki-Ogata A, Narita Y, Mii S, Ushida K, Ito M, Hirano SI, Kurokawa R, Ohno K, Usui A

General thoracic and cardiovascular surgery Vol. 68 ( 2 ) page： 158 - 163 2020.2

The oral administration of colchicine prevents the progression of aortic aneurysm Invited Reviewed

Okawa H., Yamawaki-Ogata A., Narita Y., Munakata H., Hashizume R., Usui A.

EUROPEAN HEART JOURNAL Vol. 40 page： 1882 - 1882 2019.10

Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation. Invited Reviewed

Kawai Y, Narita Y, Yamawaki-Ogata A, Usui A, Komori K

BioMed research international Vol. 2019 page： 9104680 2019

The oral administration of clarithromycin prevents the progression and rupture of aortic aneurysm. Reviewed International journal

Uchida W, Narita Y, Yamawaki-Ogata A, Tokuda Y, Mutsuga M, Lee Fujimoto K, Abe T, Oshima H, Usui A

Journal of vascular surgery Vol. 68 ( 6S ) page： 82S - 92S.e2 2018.12

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The pathogenesis of aortic aneurysm (AA) is associated with chronic inflammation in the aortic wall with increased levels of matrix metalloproteinases (MMPs). Clarithromycin (CAM) has been reported to suppresses MMP activity. In this study, we investigated whether CAM could prevent the formation and rupture of AA. METHODS: Male apolipoprotein E-deficient mice (28-30 weeks of age) were infused with angiotensin II for 28 days. CAM (100 mg/kg/d) or saline (as a control) was administered orally to the mice every day (CAM group, n = 13; control group, n = 13). After the administration period, the aortic diameter, elastin content, macrophage infiltration, MMP levels, and levels of inflammatory cytokines, including nuclear factor κB (NF-κB), were measured. RESULTS: The aortic diameter was significantly suppressed in the CAM group (P < .001). No rupture death was observed in the CAM group in contrast to five deaths (38%) in the control group (P < .01). CAM significantly suppressed the degradation of aortic elastin (56.3% vs 16.5%; P < .001) and decreased the infiltration of inflammatory macrophages (0.05 vs 0.16; P < .01). Compared with the controls, the enzymatic activity of MMP-2 and MMP-9 was significantly reduced in the CAM group (MMP-2, 0.15 vs 0.56 [P < .01]; MMP-9, 0.12 vs 0.60 [P < .01]), and the levels of interleukin 1β (346.6 vs 1066.0; P < .05), interleukin 6 (128.4 vs 346.2; P < .05), and phosphorylation of NF-κB were also decreased (0.3 vs 2.0; P < .01). CONCLUSIONS: CAM suppressed the progression and rupture of AA through the suppression of inflammatory macrophage infiltration, a reduction in MMP-2 and MMP-9 activity, and the inhibition of elastin degradation associated with the suppression of NF-κB phosphorylation.

DOI： 10.1016/j.jvs.2017.12.047