Updated on 2025/06/09

Information

 

写真a

 
KATSUKI SHUNSUKE
 
Organization
Kyushu University Hospital Coronary Care Unit Assistant Professor
School of Medicine Department of Medicine(Concurrent)
Title
Assistant Professor

Research Areas

  • Life Science / Cardiology

Degree

  • PhD ( 2014.7 Kyushu University )

  • 学士(医学) ( 2005.4 Kyushu University )

Research History

  • Kyushu University Kyushu University Hospital Coronary Care Unit  診療講師 

    2025.4 - Present

  • Kyushu University 九州大学病院循環器内科  Assistant Professor 

    2024.4 - 2025.3

  • 日本学術振興会  海外特別研究員 

    2017.4 - 2019.3

  • Brigham and Women's Hospital, Harvard Medical School  ポスドク 

    2015.10 - 2019.3

Education

  • Kyushu University   医学部   医学科

    1999.4 - 2005.3

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    Country:Japan

Research Interests・Research Keywords

  • Research theme: Inflammatory mechanisms in acute myocardial infarction

    Keyword: 急性心筋梗塞

    Research period: 2024.4

Awards

  • メンター賞

    2023.6   第129回日本循環器学会九州地方会   周産期に2度心筋梗塞を発症した重症冠攣縮性狭心症の1例

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

  • 医学科生セッションメンター賞

    2023.6   第134回日本循環器学会九州地方会   院外心肺停止を合併したST上昇型急性前壁中隔心筋梗塞の一例

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    Country:Japan

  • YIA優秀賞

    2019.12   第27回日本血管生物医学会   PCSK9 promotes macrophage activation and vein graft lesion development in LDLR-independent mechanisms: A systems approach

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    Award type:Award from Japanese society, conference, symposium, etc. 

  • Young Investigator’s Award優秀賞

    2012.3   第76回日本循環器学会学術集会   Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Plaque Destabilization and Rupture in the Brachiocephalic Arteries of ApoE-Deficient Mice through Regulating Monocyte/Macrophage Activation

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    Award type:Award from Japanese society, conference, symposium, etc.  Country:Japan

  • ATVB Travel Awards for Young Investigators

    2010.10   AHA2010  

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    Award type:Award from international society, conference, symposium, etc. 

Papers

  • The role of proprotein convertase subtilisin/kexin 9 (PCSK9) in macrophage activation: a focus on its LDL receptor-independent mechanisms Reviewed International journal

    Katsuki, S; Jha, PK; Aikawa, E; Aikawa, M

    FRONTIERS IN CARDIOVASCULAR MEDICINE   11   1431398   2024.8   ISSN:2297-055X

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    Authorship:Lead author   Language:English   Publisher:Frontiers in Cardiovascular Medicine  

    Recent clinical trials demonstrated that proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors reduce cardiovascular events without affecting systemic inflammation in the patients with coronary artery disease, as determined by high sensitivity C-reactive protein (CRP) levels. However, its pro-inflammatory effects in cardiovascular disease in humans and experimental animals beyond the traditional cholesterol receptor-dependent lipid metabolism have also called attention of the scientific community. PCSK9 may target receptors associated with inflammation other than the low-density lipoprotein receptor (LDLR) and members of the LDLR family. Accumulating evidence suggests that PCSK9 promotes macrophage activation not only via lipid-dependent mechanisms, but also lipid-independent and LDLR-dependent or -independent mechanisms. In addition to dyslipidemia, PCSK9 may thus be a potential therapeutic target for various pro-inflammatory diseases.

    DOI: 10.3389/fcvm.2024.1431398

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  • Association of Serum Levels of Cholesterol Absorption and Synthesis Markers with the Presence of Cardiovascular Disease: The CACHE Study CVD Analysis Reviewed International journal

    Katsuki Shunsuke, Matoba Tetsuya, Akiyama Yusuke, Yoshida Hiroshi, Kotani Kazuhiko, Fujii Hisako, Harada-Shiba Mariko, Ishibashi Yutaka, Ishida Tatsuro, Ishigaki Yasushi, Kabata Daijiro, Kihara Yasuki, Kurisu Satoshi, Masuda Daisaku, Matsuki Kota, Matsumura Takeshi, Mori Kenta, Nakagami Tomoko, Nakazato Masamitsu, Taniuchi Satsuki, Ueno Hiroaki, Yamashita Shizuya, Yoshida Hisako, Tsutsui Hiroyuki, Shoji Tetsuo

    Journal of Atherosclerosis and Thrombosis   30 ( 12 )   1766 - 1777   2023.12   ISSN:13403478 eISSN:18803873

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Japan Atherosclerosis Society  

    <p> <b>Aim:</b> Serum levels of cholesterol absorption and synthesis markers have been associated with cardiovascular risk in the United States and European countries. In this study, we examined the relevance of these biomarkers and the presence of cardiovascular disease (CVD) in Japanese individuals. </p><p><b>Methods:</b> The CACHE consortium, comprising of 13 research groups in Japan possessing data on campesterol, an absorption marker, and lathosterol, a synthesis marker measured by gas chromatography, compiled the clinical data using the REDCap system. </p><p><b>Results:</b> Among the 2,944 individuals in the CACHE population, those with missing campesterol or lathosterol data were excluded. This cross-sectional study was able to analyze data from 2,895 individuals, including 339 coronary artery disease (CAD) patients, 108 cerebrovascular disease (CeVD) patients, and 88 peripheral artery disease (PAD) patients. The median age was 57 years, 43% were female, and the median low-density lipoprotein cholesterol and triglyceride levels were 118 mg/dL and 98 mg/dL, respectively. We assessed the associations of campesterol, lathosterol, and the ratio of campesterol to lathosterol (Campe/Latho ratio) with the odds of CVD using multivariable-adjusted nonlinear regression models. The prevalence of CVD, especially CAD, showed positive, inverse, and positive associations with campesterol, lathosterol, and the Campe/Latho ratio, respectively. These associations remained significant even after excluding individuals using statins and/or ezetimibe. The associations of the cholesterol biomarkers with PAD were determined weaker than those with CAD. Contrarily, no significant association was noted between cholesterol metabolism biomarkers and CeVD. </p><p><b>Conclusion:</b> This study showed that both high cholesterol absorption and low cholesterol synthesis biomarker levels were associated with high odds of CVD, especially CAD.</p>

    DOI: 10.5551/jat.64119

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  • Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms Reviewed

    Shunsuke Katsuki # 1 , Prabhash K Jha # 1 , Adrien Lupieri 1 , Toshiaki Nakano 1 , Livia S A Passos 1 , Maximillian A Rogers 2 , Dakota Becker-Greene 1 , Thanh-Dat Le 1 , Julius L Decano 2 , Lang Ho Lee 2 , Gabriel C Guimaraes 1 , Ilyes Abdelhamid 2 3 , Arda Halu 2 3 , Alessandro Muscoloni 4 5 , Carlo V Cannistraci 1 5 , Hideyuki Higashi 2 , Hengmin Zhang 2 , Amélie Vromman 1 , Peter Libby 1 , C Keith Ozaki 5 , Amitabh Sharma 2 3 , Sasha A Singh 2 , Elena Aikawa 1 2 , Masanori Aikawa 1 2 3

    Circulation Research   131 ( 11 )   873 - 889   2022.11

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  • Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in <i>Apoe</i><sup>−/−</sup> Mice Reviewed International journal

    Katsuki Shunsuke, Koga Jun-ichiro, Matoba Tetsuya, Umezu Ryuta, Nakashiro Soichi, Nakano Kaku, Tsutsui Hiroyuki, Egashira Kensuke

    Journal of Atherosclerosis and Thrombosis   29 ( 1 )   111 - 125   2022.1   ISSN:13403478 eISSN:18803873

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    Authorship:Lead author   Language:English   Publisher:Japan Atherosclerosis Society  

    <p><b>Aim:</b> Abdominal aortic aneurysm (AAA) is a lethal and multifactorial disease. To prevent a rupture and dissection of enlarged AAA, prophylactic surgery and stenting are currently available. There are, however, no medical therapies preventing these complications of AAA. Statin is one of the candidates, but its efficacy on AAA formation/progression remains controversial. We have previously demonstrated that nanoparticles (NPs) incorporating pitavastatin (Pitava-NPs)—clinical trials using these nanoparticles have been already conducted—suppressed progression of atherosclerosis in apolipoprotein E-deficient ( <i>Apoe</i><sup>−/−</sup>) mice. Therefore, we have tested a hypothesis that monocytes/macrophages-targeting delivery of pitavastatin prevents the progression of AAA. </p><p><b>Methods:</b> Angiotensin II was intraperitoneally injected by osmotic mini-pumps to induce AAA formation in <i>Apoe</i><sup>−/−</sup> mice. NPs consisting of poly(lactic-co-glycolic acid) were used for <i>in vivo</i> delivery of pitavastatin to monocytes/macrophages. </p><p><b>Results:</b> Intravenously administered Pitava-NPs (containing 0.012 mg/kg/week pitavastatin) inhibited AAA formation accompanied with reduction of macrophage accumulation and monocyte chemoattractant protein-1 (MCP-1) expression. <i>Ex vivo</i> molecular imaging revealed that Pitava-NPs not only reduced macrophage accumulation but also attenuated matrix metalloproteinase activity in the abdominal aorta, which was underpinned by attenuated elastin degradation. </p><p><b>Conclusion:</b> These results suggest that Pitava-NPs inhibit AAA formation associated with reduced macrophage accumulation and MCP-1 expression. This clinically feasible nanomedicine could be an innovative therapeutic strategy that prevents devastating complications of AAA. </p>

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  • Establishment of a HFpEF model using female Dahl salt-sensitive rats: a valuable tool for elucidating the pathophysiology of HFpEF in women

    Nakashima, H; Shinohara, K; Matsumoto, S; Nakashima, R; Yoshida, D; Ono, Y; Miyamoto, R; Ikeda, S; Matsushima, S; Hashimoto, T; Katsuki, S; Ikeda, M; Yoshida, K; Kinugawa, S; Abe, K

    HYPERTENSION RESEARCH   48 ( 2 )   672 - 680   2025.2   ISSN:0916-9636 eISSN:1348-4214

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    The pathogenesis of heart failure with preserved ejection fraction (HFpEF) remains unclear, and effective treatments are limited. HFpEF is more prevalent in females, indicating potential gender differences in its pathogenesis. However, no female HFpEF model animals have been established. Hypertension is a major contributor to HFpEF, and sympathetic activation is thought to play a role in both conditions. This study aimed to establish a female HFpEF model using hypertensive Dahl salt-sensitive rats and to assess the presence of sympathetic activation. Seven-week-old female Dahl salt-sensitive rats were fed an 8% high-salt diet (HS group, n = 6), while a low-salt diet group (LS group, n = 9) served as controls. The HS group exhibited increased systolic blood pressure and heart rate. Echocardiography revealed an increased left ventricular (LV) wall thickness, a decreased E/A ratio, and an increased E/e’ ratio, all indicative of diastolic dysfunction without reduced LV ejection fraction. Additionally, the HS group showed elevated LV end-diastolic pressure, LV weight, and lung weight, along with histological cardiomyocyte hypertrophy and interstitial fibrosis. Gene expression markers for cardiac hypertrophy and fibrosis were also increased. Renal function was significantly impaired, and plasma norepinephrine levels were elevated, consistent with heightened pre-sympathetic neuronal activity in the brain. In conclusion, high salt loading from 7 weeks of age in female Dahl salt-sensitive rats induced hypertensive HFpEF phenotypes with LV hypertrophy and fibrosis, and sympathetic activation by 16 to 19 weeks of age. This model provides a valuable tool for studying HFpEF pathophysiology in women. (Figure presented.)

    DOI: 10.1038/s41440-024-02025-7

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  • Establishment of a HFpEF model using female Dahl salt-sensitive rats: a valuable tool for elucidating the pathophysiology of HFpEF in women(タイトル和訳中)

    Nakashima Hiroka, Shinohara Keisuke, Matsumoto Sho, Nakashima Ryosuke, Yoshida Daisuke, Ono Yoshiyasu, Miyamoto Ryohei, Ikeda Shota, Matsushima Shouji, Hashimoto Toru, Katsuki Shunsuke, Ikeda Masataka, Yoshida Keimei, Kinugawa Shintaro, Abe Kohtaro

    Hypertension Research   48 ( 2 )   672 - 680   2025.2   ISSN:0916-9636

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  • Prognostic impact of moderate to severe anemia associated with renal dysfunction in patients with heart failure

    Noda, E; Matsushima, S; Hashimoto, T; Tsutsui, Y; Misumi, K; Enzan, N; Yoshida, K; Shinohara, K; Fujino, T; Katsuki, S; Sakamoto, T; Hosokawa, K; Kinugawa, S; Abe, K

    SCIENTIFIC REPORTS   15 ( 1 )   3918   2025.1   ISSN:2045-2322

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    Moderate/severe anemia [hemoglobin (Hb) < 10 g/dL] is recommended to be treated in patients with renal anemia. However, the optimal therapeutic target for Hb levels in patients with heart failure (HF) is unknown. This study aimed to investigate the impact of severity of anemia, especially moderate/severe anemia, associated with renal dysfunction (RD: eGFR < 60 mL/min/1.73 m2) in HF patients. We analyzed 1,608 HF patients from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) database. Patients were classified based on the severity of admission anemia in the presence/absence of RD. Patients with RD and anemia were older, more likely to be female, and had a history of HF admission. The composite outcome was higher in RD and moderate/severe anemia (adjusted hazard ratio:2.120, 95% CI:1.559–2.881, p < 0.001) compared to RD and non/mild anemia (Hb ≥ 10 g/dL), non-RD and moderate/severe anemia, and non-RD and non/mild anemia (reference). During hospitalization, 6% and 10% of patients had improving and worsening RD and/or moderate/severe anemia, respectively. These status changes were associated with the post-discharge outcomes in HF patients. Moderate/severe anemia has a prognostic impact in HF patients with RD and may be an appropriate therapeutic target in HF.

    DOI: 10.1038/s41598-025-87650-z

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  • A Vaccine Against Fibroblast Activation Protein Improves Murine Cardiac Fibrosis by Preventing the Accumulation of Myofibroblasts

    Yoshida, S; Hayashi, H; Kawahara, T; Katsuki, S; Kimura, M; Hino, R; Sun, J; Nakamaru, R; Tenma, A; Toyoura, M; Baba, S; Shimamura, M; Katsuya, T; Morishita, R; Rakugi, H; Matoba, T; Nakagami, H

    CIRCULATION RESEARCH   136 ( 1 )   26 - 40   2025.1   ISSN:0009-7330 eISSN:1524-4571

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    BACKGROUND: Myofibroblasts are primary cells involved in chronic response-induced cardiac fibrosis. Fibroblast activation protein (FAP) is a relatively specific marker of activated myofibroblasts and a potential target molecule. This study aimed to clarify whether a vaccine targeting FAP could eliminate myofibroblasts in chronic cardiac stress model mice and reduce cardiac fibrosis. METHODS: We coadministered a FAP peptide vaccine with a cytosine-phosphate-guanine (CpG) K3 oligonucleotide adjuvant to male C57/BL6J mice and confirmed an elevation in the anti-FAP antibody titer. After continuous angiotensin II and phenylephrine administration for 28 days, we evaluated the degree of cardiac fibrosis and the number of myofibroblasts in cardiac tissues. RESULTS: We found that cardiac fibrosis was significantly decreased in the FAP-vaccinated mice compared with the angiotensin II and phenylephrine control mice (3.45±1.11% versus 8.62±4.79%; P=4.59×10−3) and that the accumulation of FAP-positive cells was also significantly decreased, as indicated by FAP immunohistochemical staining (4077±1746 versus 7327±1741 cells/mm2; FAP vaccine versus angiotensin II and phenylephrine control; P=6.67×10−3). No systemic or organ-specific inflammation due to antibody-dependent cell cytotoxicity induced by the FAP vaccine was observed. Although the transient activation of myofibroblasts has an important role in maintaining the structural robustness in the process of tissue repair, the FAP vaccine showed no adverse effects in myocardial infarction and skin injury models. CONCLUSIONS: Our study demonstrates the FAP vaccine can be a therapeutic tool for cardiac fibrosis.

    DOI: 10.1161/CIRCRESAHA.124.325017

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  • A Case of Severe COVID-19-related Pneumonia Seven Years after Heart Transplantation

    Taniguchi Gentaro, Matsushima Shouji, Fujino Takeo, Hashimoto Toru, Shinohara Keisuke, Kisanuki Hiroshi, Misumi Kayo, Katsuki Shunsuke, Shiose Akira, Abe Kohtaro

    Internal Medicine   advpub ( 0 )   2025   ISSN:09182918 eISSN:13497235

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    Language:English   Publisher:The Japanese Society of Internal Medicine  

    <p>A 67-year-old man on intense immunosuppressive therapy after heart transplantation for end-stage hypertrophic cardiomyopathy 7 years ago developed severe dyspnea and was admitted to our hospital. His serum SARS-CoV-2 antigen test was positive, and he was diagnosed with COVID-19-related pneumonia. He was started on ventilatory management for severe respiratory failure and remdesivir for COVID-19, with careful adjustment of immunosuppressive drugs. However, unexpectedly prolonged muscle weakness necessitated transfer to a rehabilitation facility. Although the COVID-19 pandemic has subsided, it is still considered a risk in post-transplant cases. Infection control is considered critical in heart transplant recipients, especially in those receiving intensified immunosuppressive drugs. </p>

    DOI: 10.2169/internalmedicine.5254-25

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  • Effect of PCSK9 inhibitor usage on coronary endothelial dysfunction in patients with hypercholesterolemia after coronary stenting: The CuVIC-2 trial

    Akiyama Y., Katsuki S., Koga Y., Yamamoto M., Hironaga K., Suematsu N., Miyata K., Mukai Y., Inoue S., Nishi J.i., Tashiro H., Nakano Y., Funakoshi K., Tagawa K., Ichi I., Tsutsui H., Abe K., Matoba T.

    Journal of Cardiology   2025   ISSN:09145087

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    Language:English   Publisher:Journal of Cardiology  

    Background: The effects of evolocumab on coronary endothelial dysfunction (CED), a hallmark of atherogenesis, are unknown. The aim of this study was to investigate whether evolocumab, in combination with high-dose statins, could ameliorate CED in patients who underwent coronary stenting. Methods: The CuVIC-2 trial was a multicenter randomized controlled trial. CED was defined as intracoronary acetylcholine (ACh)-induced contractile responses with signs of myocardial ischemia. We originally intended to enroll 160 participants but altered the study design due to the COVID-19 pandemic and then recruited 41 participants. The revised primary endpoint was the coronary contraction rate in response to ACh assessed in a core laboratory, ensuring a statistical power of over 80 % using the mixed model for repeated measures. Results: The evolocumab in combination with high-dose statins with or without ezetimibe (EV + S) group included 19 males and 4 females aged 62 ± 13 years. The high-dose statins with or without ezetimibe (S) group included 13 males and 5 females aged 64 ± 11 years. Compared with the S group, the EV + S group presented a significantly greater decrease in low-density lipoprotein cholesterol at 28 weeks; 83 ± 17 to 20 ± 16 mg/dL (−76 % from the baseline) in the EV + S group and 88 ± 16 to 81 ± 20 mg/dL (−7 % from the baseline) in the S group (p < 0.0001). At 28 weeks, there was no difference between the two groups in terms of the coronary artery constriction rate across all doses [mean difference: 4.8 % (95 % CI: −13.6 to 23.2); p = 0.6]. Conclusions: Amelioration of CED by evolocumab was not observed in this trial with several limitations.

    DOI: 10.1016/j.jjcc.2025.04.002

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  • "LIPID PARADOX" IN JAPANESE HYPERTRIGLYCERIDEMIA PATIENTS UNDERGOING PCI IN CLIDAS

    Kimura, M; Katsuki, S; Nakano, Y; Kawahara, T; Hino, R; Tabuchi, T; Fukata, M; Hieda, M; Kohro, T; Kabutoya, T; Makimoto, H; Kario, K; Imai, Y; Fujita, H; Kodera, S; Kiyosue, A; Nakayama, M; Miyamoto, Y; Tsujita, K; Sato, H; Nagai, R; Matoba, T

    ATHEROSCLEROSIS   399   2024.12   ISSN:0021-9150 eISSN:1879-1484

  • POST-PCI RISK STRATIFICATION: INSIGHTS FROM JAPANESE GUIDELINES AND CLIDAS

    Kawahara, T; Tabuchi, T; Hino, R; Kimura, M; Katsuki, S; Fukata, M; Hieda, M; Kohro, T; Kabutoya, T; Makimoto, H; Kario, K; Imai, Y; Fujita, H; Kodera, S; Kiyosue, A; Nakayama, M; Miyamoto, Y; Tsujita, K; Sato, H; Nagai, R; Matoba, T

    ATHEROSCLEROSIS   399   2024.12   ISSN:0021-9150 eISSN:1879-1484

  • Clinical and pathological characteristics of immune checkpoint inhibitor-related fulminant myocarditis

    Izumi, R; Hashimoto, T; Kisanuki, H; Ikuta, K; Otsuru, W; Asakawa, S; Yamamoto, S; Misumi, K; Fujino, T; Shinohara, K; Matsushima, S; Hosokawa, K; Katsuki, S; Mori, T; Hashisako, M; Tateishi, Y; Iwasaki, T; Oda, Y; Kinugawa, S; Abe, K

    CARDIO-ONCOLOGY   10 ( 1 )   82   2024.11   eISSN:2057-3804

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    The advent of immune checkpoint inhibitors (ICIs) has significantly improved cancer treatment. With the increasing use of ICIs, ICI-related myocarditis has been recognized. However, an evidence-based therapeutic strategy has not been established because of the limited knowledge on ICI-related myocarditis. Here, we present four cases of ICI-related fulminant myocarditis (FM). Three of the four cases resulted in fatal outcomes despite aggressive treatment with mechanical circulatory support and immunosuppressive therapy with corticosteroids. Given the poor prognosis of ICI-FM, the establishment of rapid and adequate therapeutic interventions on the basis of clinical and pathological evaluation is imperative.

    DOI: 10.1186/s40959-024-00288-0

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  • Clinical Deep Data Accumulation System (CLIDAS) reveals a "Lipid paradox" of hypertriglyceridemia in Japanese patients

    Katsuki, S; Kawahara, T; Nakano, Y; Kimura, M; Rissei, H; Matoba, T

    EUROPEAN HEART JOURNAL   45   2024.10   ISSN:0195-668X eISSN:1522-9645

  • Cyclophilin D induces necrotic core formation by mediating mitochondria-associated macrophage death in advanced atherosclerotic lesions Reviewed International journal

    Koga J.i., Umezu R., Kondo Y., Shirouzu T., Orkhonselenge N., Ueno H., Katsuki S., Matoba T., Nishimura Y., Kataoka M.

    Atherosclerosis   396   118524   2024.9   ISSN:00219150 eISSN:1879-1484

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    Background and aims: In advanced atherosclerotic lesions, macrophage deaths result in necrotic core formation and plaque vulnerability. Cyclophilin D (CypD) is a mitochondria-specific cyclophilin involved in the process of cell death after organ ischemia-reperfusion. However, the role of CypD in atherosclerosis, especially in necrotic core formation, is unknown. Therefore, this experiment aims to clarify the role of CypD in necrotic core formation. Methods: To clarify the specific role of CypD, encoded by Ppif in mice, apolipoprotein-E/CypD-double knockout (Apoe−/−Ppif−/−) mice were generated. These mice were fed a high-fat diet containing 0.15 % cholesterol for 24 weeks to accelerate atherosclerotic lesion development. Results: Deletion of CypD decreased the necrotic core size, accompanied by a reduction of macrophage apoptosis compared to control Apoe−/− mice. In RAW264.7 cells, siRNA-mediated knockdown of CypD attenuated the release of cytochrome c from the mitochondria to the cytosol induced by endoplasmic reticulum stress inducer thapsigargin. In addition, necroptosis, induced by TNF-α and caspase inhibitor, was attenuated by knockdown of CypD. Ly-6Chigh inflammatory monocytes in peripheral blood leukocytes and mRNA expression of Il1b in the aorta were decreased by deletion of CypD. In contrast, siRNA-mediated knockdown of CypD did not significantly decrease Il1b nor Ccl2 mRNA expression in RAW264.7 cells treated with LPS and IFN-γ, suggesting that inhibition of inflammation in vivo is likely due to decreased cell death in the atherosclerotic lesions rather than a direct action of CypD deletion on the macrophage. Conclusions: These results indicate that CypD induces macrophage death and mediates necrotic core formation in advanced atherosclerotic lesions. CypD could be a novel therapeutic target for treating atherosclerotic vascular diseases.

    DOI: 10.1016/j.atherosclerosis.2024.118524

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  • EVs-miR-17-5p attenuates the osteogenic differentiation of vascular smooth muscle cells potentially via inhibition of TGF-β signaling under high glucose conditions (vol 14, 16323, 2024)

    Baba, I; Matoba, T; Katsuki, S; Koga, JI; Kawahara, T; Kimura, M; Akita, H; Tsutsui, H

    SCIENTIFIC REPORTS   14 ( 1 )   19601   2024.8   ISSN:2045-2322

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    The original version of this Article contained a repeated error in the text and Figure 2 legend, where “Exo-mannitol” now reads: “EVs-mannitol” The original Article has been corrected.

    DOI: 10.1038/s41598-024-70722-x

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  • EVs-miR-17-5p attenuates the osteogenic differentiation of vascular smooth muscle cells potentially via inhibition of TGF-β signaling under high glucose conditions Reviewed International journal

    Baba, I; Matoba, T; Katsuki, S; Koga, J; Kawahara, T; Kimura, M; Akita, H; Tsutsui, H

    SCIENTIFIC REPORTS   14 ( 1 )   16323   2024.7   ISSN:2045-2322

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    Vascular calcification, which is a major complication of diabetes mellitus, is an independent risk factor for cardiovascular disease. Osteogenic differentiation of vascular smooth muscle cells (VSMCs) is one of the key mechanisms underlying vascular calcification. Emerging evidence suggests that macrophage-derived extracellular vesicles (EVs) may be involved in calcification within atherosclerotic plaques in patients with diabetes mellitus. However, the role of macrophage-derived EVs in the progression of vascular calcification is largely unknown. In this study, we investigated whether macrophage-derived EVs contribute to the osteogenic differentiation of VSMCs under high glucose conditions. We isolated EVs that were secreted by murine peritoneal macrophages under normal glucose (EVs-NG) or high glucose (EVs-HG) conditions. miRNA array analysis in EVs from murine macrophages showed that miR-17-5p was significantly increased in EVs-HG compared with EVs-NG. Prediction analysis with miRbase identified transforming growth factor β receptor type II (TGF-β RII) as a potential target of miR-17-5p. EVs-HG as well as miR-17-5p overexpression with lipid nanoparticles inhibited the gene expression of Runx2, and TGF-β RII. Furthermore, we demonstrated that VSMCs transfected with miR-17-5p mimic inhibited calcium deposition. Our findings reveal a novel role of macrophage-derived EVs in the negative regulation of osteogenic differentiation in VSMCs under high glucose conditions.

    DOI: 10.1038/s41598-024-67006-9

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  • 第5土曜特集 血管・リンパ管研究の最前線と治療への展開 血管疾患と血管を標的とした治療法 心血管病の炎症における酸化ステロールの分子生物学的役割の解明

    香月 俊輔, 的場 哲哉

    医学のあゆみ   289 ( 13 )   1134 - 1140   2024.6   ISSN:00392359

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    Publisher:医歯薬出版  

    DOI: 10.32118/ayu289131134

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  • Impact of the Coronavirus Disease 2019 (COVID-19) Pandemic on the Severity and the Mortality of Acute Myocardial Infarction in Japan — Analysis From the JROAD-DPC Database —

    Kimura Mitsukuni, Matoba Tetsuya, Nakano Yasuhiro, Katsuki Shunsuke, Sakamoto Kazuo, Nishihara Masaaki, Nagata Takuya, Tahara Yoshio, Nagao Ken, Okura Hiroyuki, Ikeda Takanori, Nakai Michikazu, Tsutsui Hiroyuki

    Circulation Reports   6 ( 6 )   191 - 200   2024.6   eISSN:24340790

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    <p><b><i>Background:</i></b> Coronavirus disease 2019 (COVID-19) has impacted on cardiovascular disease. However, it remains unclear whether the COVID-19 pandemic has impacted on disease severity and patients’ prognosis of acute myocardial infarction (AMI) in Japan.</p><p><b><i>Methods and Results:</i></b> We retrospectively accumulated data from the Japanese Registry of All Cardiac and Vascular Diseases–Diagnosis Procedure Combination (JROAD-DPC) study (April 2019 to March 2021). Patients were divided into a before COVID-19 pandemic group or a during COVID-19 pandemic group. The proportion of patients who presented with cardiogenic shock (Killip class IV) was compared between groups, in association with 30-day mortality as the primary outcome. Killip class IV AMI significantly increased in the during COVID-19 pandemic group (15.7% vs. 14.5% in the before pandemic group, P<0.0001). The 30-day mortality was higher in the during COVID-19 pandemic group (9.6% vs. 9.2% in the before COVID-19 pandemic group, P=0.049). However, there was no significant difference in the adjusted 30-day mortality in each Killip class between the before and during COVID-19 pandemic groups.</p><p><b><i>Conclusions:</i></b> During the early stage of the COVID-19 pandemic in Japan, 30-day mortality of AMI increased, mainly because of the increase of Killip class IV AMI patients. However, irrespective of the COVID-19 pandemic, the adjusted 30-day mortality of each Killip classification group was unchanged.</p>

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  • COVID-19パンデミックが日本の急性心筋梗塞の重症度と死亡率に及ぼした影響 JROAD-DPCデータベースの分析(Impact of the Coronavirus Disease 2019(COVID-19) Pandemic on the Severity and the Mortality of Acute Myocardial Infarction in Japan: Analysis From the JROAD-DPC Database)

    Kimura Mitsukuni, Matoba Tetsuya, Nakano Yasuhiro, Katsuki Shunsuke, Sakamoto Kazuo, Nishihara Masaaki, Nagata Takuya, Tahara Yoshio, Nagao Ken, Okura Hiroyuki, Ikeda Takanori, Nakai Michikazu, Tsutsui Hiroyuki

    Circulation Reports   6 ( 6 )   191 - 200   2024.6

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    COVID-19パンデミックが日本の急性心筋梗塞(AMI)患者の重症度や予後に及ぼした影響を後ろ向きに評価した。全国規模の診療情報データベースである循環器疾患診療実態調査(JROAD-DPC)の2019年4月~2021年3月のデータからAMI患者84786例を抽出し、これらをパンデミック前群42607例(女性26.5%、年齢中央値71歳)とパンデミック後群42179例(女性26.9%、年齢中央値72歳)に分けた。主要評価項目は入院から30日以内の死亡率(30日死亡率)であり、AMIの重症度(Killip分類)と院内処置も評価した。その結果、心原性ショック(Killip分類IV)を呈したAMI患者の割合は、パンデミック前群が14.5%、パンデミック後群が15.7%で、有意に増加していた。30日死亡率は、パンデミック前群が9.2%、パンデミック後群が9.6%で有意な増加がみられた。しかし、Killip分類で調整後の30日死亡率には両群間で有意差は認められなかった。

  • Overview of the 87<sup>th</sup> Annual Scientific Meeting of the Japanese Circulation Society (JCS2023) ― New Challenge With Next Generation ―

    Matoba Tetsuya, Nakano Yasuhiro, Katsuki Shunsuke, Ide Tomomi, Matsushima Shouji, Fujino Takeo, Hashimoto Toru, Shinohara Keisuke, Abe Kohtaro, Hosokawa Kazuya, Sakamoto Takafumi, Sakamoto Ichiro, Kakino Takamori, Ishikita Ayako, Nishizaki Akiko, Sakamoto Kazuo, Takase Susumu, Nagayama Tomomi, Tohyama Takeshi, Nagata Takuya, Kinugawa Shintaro, Tsutsui Hiroyuki

    Circulation Journal   88 ( 4 )   615 - 619   2024.3   ISSN:13469843 eISSN:13474820

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    <p>The 87<sup>th</sup>Annual Meeting of the Japanese Circulation Society (JCS2023) was held in March 2023 in Fukuoka, Japan, marking the first in-person gathering after the COVID-19 pandemic. With the theme of “New Challenge With Next Generation” the conference emphasized the development of future cardiovascular leaders and technologies such as artificial intelligence (AI). Notable sessions included the Mikamo Lecture on heart failure and the Mashimo Lecture on AI in medicine. Various hands-on sessions and participatory events were well received, promoting learning and networking. Post-event surveys showed high satisfaction among participants, with positive feedback on face-to-face interactions and the overall experience. JCS2023, attended by 17,852 participants, concluded successfully, marking a significant milestone in post-pandemic meetings, and advancing cardiovascular medicine.</p>

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  • 血清中のコレステロール吸収・合成マーカー濃度が表す心血管疾患の存在との関連性 CACHE研究CVD解析(Association of Serum Levels of Cholesterol Absorption and Synthesis Markers with the Presence of Cardiovascular Disease: The CACHE Study CVD Analysis)

    Katsuki Shunsuke, Matoba Tetsuya, Akiyama Yusuke, Yoshida Hiroshi, Kotani Kazuhiko, Fujii Hisako, Harada-Shiba Mariko, Ishibashi Yutaka, Ishida Tatsuro, Ishigaki Yasushi, Kabata Daijiro, Kihara Yasuki, Kurisu Satoshi, Masuda Daisaku, Matsuki Kota, Matsumura Takeshi, Mori Kenta, Nakagami Tomoko, Nakazato Masamitsu, Taniuchi Satsuki, Ueno Hiroaki, Yamashita Shizuya, Yoshida Hisako, Tsutsui Hiroyuki, Shoji Tetsuo

    Journal of Atherosclerosis and Thrombosis   30 ( 12 )   1766 - 1777   2023.12   ISSN:1340-3478

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    日本人集団において、コレステロールの吸収・合成に関わる血清中のバイオマーカー類と心血管疾患(CVD)の存在との関連性を検討した。国内13の研究グループで構成されるCACHE Consortiumが所有している2895名(女性43%、年齢中央値57歳)の臨床データを解析対象とした。本集団には冠動脈疾患の患者339名、脳血管疾患の108名、末梢動脈疾患の88名が含まれていた。統計解析の結果、CVDの存在、中でも冠動脈疾患の存在は、カンペステロール(C)と正に、ラトステロール(L)と負に、C/L比とは正に関連していることが示された。こうした関連性は、スタチン薬またはエゼチミブを使用している集団を除外した場合でも依然として有意な関連性として観察された。末梢動脈疾患とコレステロール関連バイオマーカー類との関連性は、冠動脈疾患と同マーカー類の関連性よりも弱かった。脳血管疾患と同マーカー類の間には有意な関連性は検出されなかった。本研究結果から、コレステロールの高吸収および低合成を表すバイオマーカーのレベルはCVDの高オッズ、特に冠動脈疾患の高オッズと関連していることが明らかになった。

  • Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial Reviewed International journal

    Nakano Yasuhiro, Yamamoto Mitsutaka, Matoba Tetsuya, Katsuki Shunsuke, Nakashiro Soichi, Takase Susumu, Akiyama Yusuke, Nagata Takuya, Mukai Yasushi, Inoue Shujiro, Oi Keiji, Higo Taiki, Takemoto Masao, Suematsu Nobuhiro, Eshima Kenichi, Miyata Kenji, Usui Makoto, Sadamatsu Kenji, Kadokami Toshiaki, Hironaga Kiyoshi, Ichi Ikuyo, Todaka Koji, Kishimoto Junji, Tsutsui Hiroyuki

    Journal of Atherosclerosis and Thrombosis   30 ( 8 )   907 - 918   2023.8   ISSN:13403478 eISSN:18803873

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    <p> <b>Aim:</b> Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial.</p><p><b>Methods:</b> The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S+E). We enrolled 79 patients (S group, 39 patients; S+E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6–8 months of follow-up.</p><p><b>Results:</b> After the treatment period, the S+E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9±3.7 vs. 67.7±3.8 mg/dL, <i>p</i>=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (β-epoxycholesterol, 4β-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S+E group. IVUS analyses revealed greater plaque regression in the S+E group than in the S group (−6.14% vs. −1.18% for each group, <i>p</i>=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression.</p><p><b>Conclusions:</b> Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.</p>

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  • スタチンおよびエゼチミブによる脂質低下療法中の血清オキシステロールと冠動脈プラーク退縮との関連性 CuVIC試験からの知見(Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial)

    Nakano Yasuhiro, Yamamoto Mitsutaka, Matoba Tetsuya, Katsuki Shunsuke, Nakashiro Soichi, Takase Susumu, Akiyama Yusuke, Nagata Takuya, Mukai Yasushi, Inoue Shujiro, Oi Keiji, Higo Taiki, Takemoto Masao, Suematsu Nobuhiro, Eshima Kenichi, Miyata Kenji, Usui Makoto, Sadamatsu Kenji, Kadokami Toshiaki, Hironaga Kiyoshi, Ichi Ikuyo, Todaka Koji, Kishimoto Junji, Tsutsui Hiroyuki

    Journal of Atherosclerosis and Thrombosis   30 ( 8 )   907 - 918   2023.8   ISSN:1340-3478

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    冠動脈ステント留置術を受けた冠動脈疾患の患者をスタチン(S)またはSとエゼチミブの併用(S+E)で治療するCuVIC試験から、治療前と6~8ヵ月追跡調査後の非責任病変の血管内超音波(IVUS)画像が得られた79症例(S群39名、S+E群40名)を抽出し解析した。治療期間後のS+E群のLDL-コレステロール(LDL-C)値はS群と比べて有意に低かった。S+E群ではコレステロール吸収のマーカーであるcampesterol、オキシステロール(β-epoxycholesterol、4β-hydroxycholesterol、27-hydroxycholesterol)も低かった。IVUS解析でS+E群のプラーク退縮率はS群と比べて大きかった。campesterolおよび27-hydroxycholesterolの低下はプラーク退縮と正相関し、LDL-Cの低下は相関しなかった。

  • Temporal Trends in Antithrombotic Therapy for Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention From 2014 to 2022 in Japan Reviewed

    Nakano Yasuhiro, Matoba Tetsuya, Yamamoto Mitsutaka, Katsuki Shunsuke, Koga Yasuaki, Mukai Yasushi, Inoue Shujiro, Suematsu Nobuhiro, Higo Taiki, Takemoto Masao, Miyata Kenji, Usui Makoto, Kadokami Toshiaki, Tashiro Hideki, Morishige Kunio, Hironaga Kiyoshi, Tsutsui Hiroyuki, for the QcVIC Investigators

    Circulation Reports   5 ( 7 )   282 - 288   2023.7   eISSN:24340790

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    <p><b><i>Background:</i></b> Recent revisions of clinical guidelines by the Japanese Circulation Society, American Heart Association/American College of Cardiology, and European Society of Cardiology updated the management of antithrombotic strategies for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI). However, the extent to which these guidelines have been implemented in real-world daily clinical practice is unclear.</p><p><b><i>Methods and Results:</i></b> We conducted surveys on the status of antithrombotic therapy for patients with AF undergoing PCI every 2 years from 2014 to 2022 in 14 cardiovascular centers in Japan. The primary use of drug-eluting stents increased from 10% in 2014 to 95–100% in 2018, and the use of direct oral anticoagulants increased from 15% in 2014 to 100% in 2018, in accordance with the revised practice guidelines. In patients with acute coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2018, and increased to >70% from 2020. In patients with chronic coronary syndrome, the duration of triple therapy within 1 month was approximately 10% until 2016, and >75% from 2018. Since 2020, the most common timing of discontinuation of dual antiplatelet therapy to transition to anticoagulation monotherapy during the chronic phase of PCI has been 1 year after PCI.</p><p><b><i>Conclusions:</i></b> Japanese interventional cardiologists have updated their treatment strategies for patients with AF undergoing PCI according to revisions of clinical practice guidelines.</p>

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  • Association of Serum Oxysterols with Cholesterol Metabolism Markers and Clinical Factors in Patients with Coronary Artery Disease: A Covariance Structure Analysis Reviewed International journal

    Akiyama, Y; Katsuki, S; Matoba, T; Nakano, Y; Takase, S; Nakashiro, S; Yamamoto, M; Mukai, Y; Inoue, S; Oi, K; Higo, T; Takemoto, M; Suematsu, N; Eshima, K; Miyata, K; Usui, M; Sadamatsu, K; Kadokami, T; Hironaga, K; Ichi, I; Todaka, K; Kishimoto, J; Tsutsui, H

    NUTRIENTS   15 ( 13 )   2023.7   eISSN:2072-6643

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    Oxysterols have been implicated in the pathogenesis of cardiovascular diseases. Serum levels of oxysterols could be positively correlated with cholesterol absorption and synthesis. However, physiological regulation of various serum oxysterols is largely unknown. The aim of this study was to investigate the relationship between clinical factors and cholesterol metabolism markers, and identify oxysterols associated with cholesterol absorption and synthesis in patients with coronary artery disease. Subjects (n = 207) who underwent coronary stenting between 2011 and 2013 were studied cross-sectionally. We measured lipid profiles including serum oxysterols. As for the serum biomarkers of cholesterol synthesis and absorption, oxysterol levels were positively correlated with campesterol and lathosterol. Covariance structure analysis revealed that dyslipidemia and statin usage had a positive correlation with “cholesterol absorption”. Statin usage also had a positive correlation with “cholesterol synthesis”. Several oxysterols associated with cholesterol absorption and/or synthesis. In conclusion, we elucidated the potential clinical factors that may affect cholesterol metabolism, and the associations between various oxysterols with cholesterol absorption and/or synthesis in patients with coronary artery disease.

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  • 国内で経皮的冠動脈インターベンションを受ける心房細動患者への抗血栓療法に関する2014~2022年の経時的傾向(Temporal Trends in Antithrombotic Therapy for Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention From 2014 to 2022 in Japan)

    Nakano Yasuhiro, Matoba Tetsuya, Yamamoto Mitsutaka, Katsuki Shunsuke, Koga Yasuaki, Mukai Yasushi, Inoue Shujiro, Suematsu Nobuhiro, Higo Taiki, Takemoto Masao, Miyata Kenji, Usui Makoto, Kadokami Toshiaki, Tashiro Hideki, Morishige Kunio, Hironaga Kiyoshi, Tsutsui Hiroyuki

    Circulation Reports   5 ( 7 )   282 - 288   2023.7

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    日本国内の心血管センター14施設において経皮的冠動脈インターベンション(PCI)を受ける心房細動(AF)患者への抗血栓療法の状況を、2014~2022年にかけて2年毎に調査した。本大学の協力施設である上記14施設の心臓インターベンション専門医(CI医)に対し、PCIを施行されるAF症例への抗血栓療法について2年置きの質問票調査を行った。薬剤溶出ステントを初回使用すると回答された率は2014年の10%から2018年には95~100%へ、直接経口抗凝固薬の使用は2014年の15%から2018年には100%へと上昇していた。これらの使用率上昇の動向は、最近改訂された、日本・米国・欧州の3学会による臨床ガイドラインに沿ったものであった。急性冠症候群の患者のシナリオを提示した場合、3剤併用療法を施行する期間の長さを1ヵ月以内と回答した率は2018年までは10%であったのに対し、2020年は70%超へと上昇していた。慢性冠症候群のシナリオでは、上記の回収率は2016年までは約10%、2018年以降は75%超へ上昇した。PCIの慢性期に抗血小板薬2剤併用療法を中止し単剤療法へと移行するタイミングとして、2020年以降、最も回答が多かったのは、PCI後1年であった。日本のCI医は、臨床診療ガイドラインの改訂に合わせ、PCI施行AF患者に対しての自身の治療戦略も最新のものに更新していた。

  • Histologic Diagnosis of Coronary Amyloidosis Using Percutaneous Transluminal Directional Atherectomy

    Yoshida, D; Hashimoto, T; Katsuki, M; Ishikita, A; Ishikawa, Y; Fujino, T; Shinohara, K; Matsushima, S; Kinugawa, S; Nakano, Y; Katsuki, S; Matoba, T; Hayashidani, S; Tsutsui, H

    CJC OPEN   5 ( 1 )   99 - 102   2023.1   ISSN:2589-790X

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  • Dietary 7-ketocholesterol exacerbates myocardial ischemia-reperfusion injury in mice through monocyte/macrophage-mediated inflammation Reviewed International journal

    Uchikawa, T; Matoba, T; Kawahara, T; Baba, I; Katsuki, S; Koga, J; Hashimoto, Y; Yamasaki, R; Ichi, I; Akita, H; Tsutsui, H

    SCIENTIFIC REPORTS   12 ( 1 )   14902   2022.9   ISSN:2045-2322

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    Emerging evidence suggests that 7-ketocholesterol (7-KC), one of the most abundant dietary oxysterols, causes inflammation and cardiovascular diseases. Here we show the deteriorating effects of dietary 7-KC on myocardial ischemia–reperfusion (IR) injury and detailed the molecular mechanisms. A high-fat high-cholesterol diet containing 7-KC (7KWD) for 3 weeks increased the plasma 7-KC level compared with high-fat high-cholesterol diet in mice. In wild-type mice but not in CCR2−/− mice, dietary 7-KC increased the myocardial infarct size after IR. Flow cytometry revealed that the ratio of Ly-6Chigh inflammatory monocytes to total monocytes was increased in the 7KWD group. Unbiased RNA sequencing using murine primary macrophages revealed that 7-KC regulated the expression of transcripts related to inflammation and cholesterol biosynthesis. We further validated that in vitro, 7-KC induced endoplasmic reticulum stress, mitochondrial reactive oxygen species production, and nuclear factor-kappa B activation, which are associated with increased mRNA levels of proinflammatory cytokines. Administration of N-acetyl-l-cysteine or siRNA-mediated knockdown of PKR-like endoplasmic reticulum kinase or endoplasmic reticulum oxidase 1α suppressed the levels of 7-KC-induced inflammation. Dietary 7-KC exacerbates myocardial IR injury through monocyte/macrophage-mediated inflammation. Endoplasmic reticulum stress and oxidative stress are involved in the 7-KC-induced proinflammatory response in macrophages.

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  • Mitochondrial Uncoupling: A Fine-Tuning Knob for Mitochondria-Targeting Therapeutics for Coronary Artery Disease

    Katsuki Shunsuke, Koga Jun-ichiro

    Journal of Atherosclerosis and Thrombosis   29 ( 6 )   811 - 813   2022.6   ISSN:13403478 eISSN:18803873

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    <p> <b>Aim:</b> Atherosclerosis is responsible for high morbidity and mortality rates around the world. Local arterial oxidative stress is involved in all phases of atherosclerosis development. Mitochondria is a relevant source of the oxidants, particularly under certain risky conditions, such as hypercholesterolemia. The aim of this study was to test whether lowering the production of mitochondrial oxidants by induction of a mild uncoupling can reduce atherosclerosis in hypercholesterolemic LDL receptor knockout mice.</p><p> <b>Methods:</b> The mice were chronically treated with very low doses of DNP (2,4-dinitrophenol) and metabolic, inflammatory and redox state markers and atherosclerotic lesion sizes were determined.</p><p><b>Results:</b> The DNP treatment did not change the classical atherosclerotic risk markers, such as plasma lipids, glucose homeostasis, and fat mass, as well as systemic inflammatory markers. However, the DNP treatment diminished the production of mitochondrial oxidants, systemic and tissue oxidative damage markers, peritoneal macrophages and aortic rings oxidants generation. Most importantly, development of spontaneous and diet-induced atherosclerosis (lipid and macrophage content) were significantly decreased in the DNP-treated mice. In vitro, DNP treated peritoneal macrophages showed decreased H<sub>2</sub>O<sub>2</sub> production, increased anti-inflammatory cytokines gene expression and secretion, increased phagocytic activity, and decreased LDL-cholesterol uptake.</p><p><b>Conclusions:</b> These findings are a proof of concept that activation of mild mitochondrial uncoupling is sufficient to delay the development of atherosclerosis under the conditions of hypercholesterolemia and oxidative stress. These results promote future approaches targeting mitochondria for the prevention or treatment of atherosclerosis.</p>

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  • Comparison of Endothelial Dysfunction in Coronary Arteries with Bare Metal and 2<sup>nd</sup>-Generation Drug-Eluting Stents Reviewed International journal

    Akiyama Yusuke, Matoba Tetsuya, Katsuki Shunsuke, Takase Susumu, Nakashiro Soichi, Nakano Yasuhiro, Noma Kensuke, Tsutsui Hiroyuki

    Journal of Atherosclerosis and Thrombosis   29 ( 3 )   379 - 392   2022.3   ISSN:13403478 eISSN:18803873

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    <p><b>Aims:</b> Previous studies suggested that implantation with a 1st-generation DES was associated with coronary endothelial dysfunction, which was associated with Rho-kinase activation. Second-generation drug-eluting stents (DESs) may preserve coronary endothelial function in stented coronary arteries; however, because of methodological limitations, further study is needed to clarify the association between 2 <sup>nd</sup>-generation DESs and coronary endothelial dysfunction. </p><p><b>Methods:</b> We retrospectively analysed the CuVIC trial database, where we identified 112 patients who underwent coronary stenting in the left coronary arteries with either a bare metal stent (BMS, <i>n</i>=53) or 2<sup>nd</sup>-generation DES (<i>n</i>=59). We compared vasomotions of target vessels with stents and non-target vessels without stents. Furthermore, we measured the Rho-kinase activation detected in mononucleocytes from aortic and coronary sinus blood. </p><p><b>Results:</b> ACh-induced vasoconstrictive responses of target vessels were not enhanced with a 2<sup>nd</sup>-generation DES (45±21% vs. 44±20%, <i>P</i>=0.56, paired <i>t</i>-test), but significantly enhanced in the coronary arteries with a BMS (50±18% vs. 42±20%, <i>P</i>=0.002). Rho-kinase activation did not differ between patients with a BMS and 2<sup>nd</sup>-generation DES. In the target vessels with a BMS, large late lumen loss and acute coronary syndrome (ACS) at the index percutaneous coronary intervention (PCI) were associated with ACh-induced enhanced coronary vasoconstrictive responses. </p><p><b>Conclusions:</b> Evaluation of ACh-induced vasomotion of target vessels comparing with non-target vessels revealed that 2<sup>nd</sup>-generation DESs were not associated with coronary endothelial dysfunction in target vessels, nor activation of Rho-kinase in the coronary sinus blood 6-8 months after stenting. </p>

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  • ベアメタルステントまたは第2世代薬剤溶出性ステントを留置した冠動脈における内皮機能障害の比較(Comparison of Endothelial Dysfunction in Coronary Arteries with Bare Metal and 2nd-Generation Drug-Eluting Stents)

    Akiyama Yusuke, Matoba Tetsuya, Katsuki Shunsuke, Takase Susumu, Nakashiro Soichi, Nakano Yasuhiro, Noma Kensuke, Tsutsui Hiroyuki

    Journal of Atherosclerosis and Thrombosis   29 ( 3 )   379 - 392   2022.3   ISSN:1340-3478

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    Language:English   Publisher:(一社)日本動脈硬化学会  

    左冠動脈の狭窄病変に対してステント留置術を施行した患者112例(男性86例、女性26例)を対象に、ベアメタルステントまたは第2世代薬剤溶出性ステントの留置が冠動脈内皮機能障害に及ぼす影響を比較した。対象はコレステロール吸収阻害薬による冠動脈ステント標的血管の機能改善効果(CuVIC)試験に登録された患者で、標的血管不全を呈した症例は除外した。患者を留置ステントに応じて、ベアメタルステント(BMS)群53例(男性87%、平均64±11歳)と第2世代薬剤溶出性ステント(DES)群59例(男性68%、平均67±9歳)の2群に分類した。患者背景に有意な群間差はなかった。アセチルコリン負荷下でステント留置した標的血管と非標的血管における攣縮性を比較したところ、BMS群は標的血管(50±18%)の方が非標的血管(42±20%)より冠攣縮が有意に高かったが(P=0.002)、DES群で有意差はなかった。大動脈および冠静脈洞で採血した末梢血単核球のRho kinase活性はBMS群とDES群の間に有意差はなかった。BMS群で標的血管における冠攣縮の関連因子として、晩期内腔損失と冠症候群の既往が同定された。

  • ナノ粒子によるピタバスタチンの単球/マクロファージへの送達はApoe欠損マウスにおけるアンジオテンシンII誘発性腹部大動脈瘤の形成を抑制する(Nanoparticle-Mediated Delivery of Pitavastatin to Monocytes/Macrophages Inhibits Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Apoe-/- Mice)

    Katsuki Shunsuke, Koga Jun-ichiro, Matoba Tetsuya, Umezu Ryuta, Nakashiro Soichi, Nakano Kaku, Tsutsui Hiroyuki, Egashira Kensuke

    Journal of Atherosclerosis and Thrombosis   29 ( 1 )   111 - 125   2022.1   ISSN:1340-3478

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    Language:English   Publisher:(一社)日本動脈硬化学会  

    アポリポ蛋白E欠損(Apoe-/-)マウスにおける腹部大動脈瘤(AAA)に対して、ポリ乳酸とポリグリコール酸の共重合体から成るナノ粒子(NP)を用いたピタバスタチンの単球/マクロファージへの送達による効果を検討した。浸透圧ミニポンプによってApoe-/-マウスにアンジオテンシンIIを腹腔内注射し、AAA形成を誘導した。ピタバスタチン保持NPを静脈内投与したところ、マクロファージの蓄積および単球走化性タンパク質-1(MCP-1)の発現が抑制され、AAA形成が阻害された。Ex vivo分子イメージングにより、ピタバスタチン保持NPはマクロファージの蓄積を減少させるだけでなく、腹部大動脈におけるマトリックスメタロプロテアーゼ活性を低下させた。それはエラスチン分解の減少で支持された。以上より、ピタバスタチン保持NPは、マクロファージの蓄積とMCP-1発現を抑制することで、AAA形成を阻害することが示唆された。

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Books

  • モデル動物の作製と利用-循環器疾患2021

    香月俊輔、的場哲哉、古賀純一郎、江頭健輔、筒井裕之(第Ⅰ部 心臓・血管・止血系 第3章 冠動脈・血管疾患 第4節 粥状動脈硬化プラーク破綻モデル)

    日本エスエルシー株式会社  2021.9 

  • モデル動物利用マニュアル

    香月俊輔、的場哲哉、江頭健輔(第5章 循環器疾患 第1節 心疾患 第8項 Plaque Ruptureモデル)

    日本エスエルシー株式会社  2010.8 

Presentations

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MISC

Professional Memberships

  • ESC

  • 日本心血管インターベンション治療学会(CVIT)

  • 日本動脈硬化学会

  • 日本血管生物医学会

  • 日本循環器学会

  • 日本内科学会

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Committee Memberships

  • 日本血管生物医学会   評議員  

       

  • 日本動脈硬化学会   評議員  

       

Research Projects

  • 慢性腎臓病による血管石灰化における単球/マクロファージの役割の解明

    Grant number:23K07531  2023.4 - 2026.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    香月 俊輔

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    Authorship:Principal investigator  Grant type:Scientific research funding

    血管石灰化は血管病の形成過程において、糖尿病などによる粥状動脈硬化形成過程として、加齢や慢性腎臓病では動脈硬化とは独立して生じる病態であるが、心血管死の高リスクと関連し、喫緊の解決すべき医学的課題である。本研究の目的は血管石灰化病変において、classical monocyte/M1マクロファージ(classically activated macrophage)、non-classical monocyte/M2マクロファージ(alternatively activated macrophage)が異なる役割を果たし、前者が新生内膜石灰化、後者が中膜石灰化に関与するという仮説の証明にある。

    CiNii Research

  • The role of reparative monocytes in tissue repair during left ventricular remodeling after myocardial infarction

    Grant number:20K17086  2020.4 - 2024.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Early-Career Scientists

    Katsuki Shunsuke

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    Authorship:Principal investigator  Grant type:Scientific research funding

    The increasing incidence of heart failure in patients following acute myocardial infarction remains an unresolved medical challenge. We aimed to elucidate the mechanisms of cardiac tissue repair by reparative monocytes in left ventricular remodeling through the depletion of inflammatory monocytes using Ly-6C vaccination. Following myocardial infarction in Red-green mice, we confirmed the accumulation of RFP-positive CCR2-positive monocytes on day 3 and GFP-positive CX3CR1-positive monocytes on day 7 in the ischemic myocardium. To deplete inflammatory monocytes, we developed a Ly-6C vaccination to induce Ly-6C antibody production in the blood, which resulted in a decrease in Ly-6C monocytes in peripheral blood upon vaccination. Building upon this research, we will elucidate the mechanisms underlying the accumulation of reparative monocytes in the post-infarction myocardium in the future.

    CiNii Research

  • 慢性腎臓病の血管石灰化に対する新規ワクチン治療の開発

    2023.4 - 2024.3

    臨床研究奨励基金 臨床研究助成 

  • マクロファージ由来エクソソーム中マイクロRNAによる糖尿病血管石灰化制御

    2022.4 - 2024.3

    MSD生命科学財団研究助成 (生活習慣病領域) 

  • Role of Oxysterol in cardiovascular inflammation: Discovery of molecular mechanisms and therapeutic targets.

    Grant number:23K21434  2021.4 - 2025.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    的場 哲哉, 仲野 泰啓, 香月 俊輔, 古賀 純一郎

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    Authorship:Coinvestigator(s)  Grant type:Scientific research funding

    酸化ステロールはコレステロールが保存や調理による加熱、さらに体内での酸化ストレスによって変性した物質で、心臓や血管に炎症を起こし、動脈硬化や心不全の原因となることが徐々に明らかになってきています。この研究は、臨床研究において、心筋梗塞などの冠動脈疾患患者の血液中の酸化ステロール量と病状の関わりを解明するとともに、基礎研究において、酸化ステロールが心血管病を起こすメカニズムを明らかにし、治療法開発のターゲットを検討しています。

    CiNii Research

  • 腹部大動脈瘤に対する革新的ナノ治療の開発

    2019.4 - 2020.3

    興和生命科学振興財団研究助成 

  • ナノ粒子技術を基盤とした心筋虚血再灌流治療の開発

    2014.4 - 2015.3

    興和生命科学振興財団研究助成 

  • 炎症性単球の炎症制御による粥状動脈硬化プラーク破綻予防療法の研究開発

    Grant number: 25860607  2013.4 - 2015.3

    科学研究費助成事業  

    香月俊輔

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Educational Activities

  • 虚血性心疾患(狭心症・急性心筋梗塞)に関する医学部学生講義
    医学部学生病院実習の指導
    医学部学生OSCE関連業務

Class subject

  • 3学年系統医学II(循環器)

    2024.12 - Present  

Travel Abroad

  • 2015.10 - 2019.3

    Staying countory name 1:United States   Staying institution name 1:Brigham and Women's Hospital, Harvard Medical School

Specialized clinical area

  • Biology / Medicine, Dentistry and Pharmacy / Internal Medicine / Cardiology

Clinician qualification

  • Certifying physician

    日本心血管インターベンション治療学会(CVIT)

  • Specialist

    The Japanese Circulation Society(JCS)

  • Specialist

    The Japanese Society of Internal Medicine(JSIM)

  • Specialist

    日本動脈硬化学会

Year of medical license acquisition

  • 2005