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Tetsuya Matoba Last modified date:2018.06.18

Lecturer / Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences
Angiocardiology
Kyushu University Hospital


Graduate School
Undergraduate School
Administration Post
Other


E-Mail
Phone
092-642-5360
Fax
092-642-5374
Academic Degree
MD, PhD
Field of Specialization
Cardiovascular Medicine, Vascular biology
Outline Activities
Research in vascular biology, clinical cardiology and resuscitation science
Education in basic vascular biology, clinical cardiology and resuscitation
Clinical practice in interventional cardiology
Research
Research Interests
  • Role of extracellular vesicles in cardiovascular diseases; Development of new therapeutic strategy
    keyword : exosome, atherosclerosis, myocardial infarction
    2017.10~2022.03.
  • Roles of oxidized lipids including oxysterols in the development of atherosclerotic cardiovascular disease
    keyword : atherosclerosis, oxysterol, endothelial function
    2011.04~2020.03.
  • Development of new therapeutic modality targeting inflammatory monocyte/macrophage in cardiovascular disease
    keyword : inflammation, monocyte, macrophage, atherosclerosis, acute coronary syndrome
    2012.04~2019.03.
  • Monocyte-selective nanoparticle-mediated drug delivery system for treatment of atherosclerotic plaque rupture
    keyword : atherosclerosis macrophage nanoparticle
    2008.04~2011.03.
Academic Activities
Papers
1. Honda, Katsuya; Matoba, Tetsuya; Antoku, Yoshibumi; Koga, Jun-ichiro; Ichi, Ikuyo; Nakano, Kaku; Tsutsui, Hiroyuki; Egashira, Kensuke, Lipid-Lowering Therapy With Ezetimibe Decreases Spontaneous Atherothrombotic Occlusions in a Rabbit Model of Plaque Erosion: A Role of Serum Oxysterols, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 10.1161/ATVBAHA.117.310244, 38, 4, 757-771, 2018.04, [URL], OBJECTIVE:Plaque erosion is increasing its importance as one of the mechanisms of acute coronary syndromes in this statin era. However, the clinical efficacy of currently used lipid-lowering agents in the prevention of thrombotic complications associated with plaque erosion has not been clarified. Therefore, we examined the therapeutic effects of ezetimibe or rosuvastatin monotherapy on spontaneous atherothrombotic occlusion.

APPROACH AND RESULTS:Femoral arteries of Japanese white rabbits, fed a high-cholesterol diet, were injured by balloon catheter, and then angiotensin II was continuously administrated. In 94% of these arteries, spontaneous thrombotic occlusions were observed after 5 weeks (median) of balloon injury. Histochemical analyses indicated that the injured arteries had similar pathological features to human plaque erosions; (1) spontaneous thrombotic occlusion, (2) lack of endothelial cells, and (3) tissue factor expression in vascular smooth muscle cells. Ezetimibe (1.0 mg/kg per day), but not rosuvastatin (0.6 mg/kg per day), significantly decreased thrombotic occlusion of arteries accompanied with accelerated re-endothelialization and the decreases of serum oxysterols despite the comparable on-treatment serum cholesterol levels. The 7-ketocholesterol inhibited the migration of human umbilical vein endothelial cells. Both 7-ketocholesterol and 27-hydroxycholesterol increased tissue factor expression in cultured rat vascular smooth muscle cells. Tissue factor expression was also induced by serum from vehicle- or rosuvastatin-treated rabbits, but the induction was attenuated with serum from ezetimibe-treated rabbits.

CONCLUSIONS:We have established a novel rabbit model of spontaneous atherothromobotic occlusion without plaque rupture that is feasible to test the therapeutic effects of various pharmacotherapies. Ezetimibe may decrease atherothrombotic complications after superficial plaque erosion by reducing serum oxysterols..
2. Tetsuya Matoba, Susumu Takase, Soichi Nakashiro, Yasushi Mukai, Inoue Shujiro, Keiji Oi, Taiki Higo, Shunsuke Katsuki, Masao Takemoto, Nobuhiro Suematsu, Kenichi Eshima, Kenji Miyata, SHinji Satoh, Toshiaki Kadokami, Kiyoshi Hironaga, Ikuyo Ichi, Koji Todaka, Junji Kishimoto, Egashira kensuke, Ezetimibe in Combination With Statins Ameliorates Endothelial Dysfunction in Coronary Arteries After Stenting: The CuVIC Trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction After Coronary Stenting), a Multicenter Randomized Controlled Trial., Arteriosclerosis, Thrombosis, and Vascular Biology, 10.1161/ATVBAHA.116.308388, 37, 2, 350-358, 2017.02, [URL], OBJECTIVES:We sought to investigate whether treatment with ezetimibe in combination with statins improves coronary endothelial function in target vessels in coronary artery disease patients after coronary stenting.

APPROACH AND RESULTS:We conducted a multicenter, prospective, randomized, open-label, blinded-end point trial among 11 cardiovascular treatment centers. From 2011 to 2013, 260 coronary artery disease patients who underwent coronary stenting were randomly allocated to 2 arms (statin monotherapy, S versus ezetimibe [10 mg/d]+statin combinational therapy, E+S). We defined target vessel dysfunction as the primary composite outcome, which comprised target vessel failure during treatment and at the 6- to 8-month follow-up coronary angiography and coronary endothelial dysfunction determined via intracoronary acetylcholine testing performed in cases without target vessel failure at the follow-up coronary angiography. Coadministration of ezetimibe with statins further lowered low-density lipoprotein cholesterol levels (83±23 mg/dL in S versus 67±23 mg/dL in E+S; P<0.0001), with significant decreases in oxidized low-density lipoprotein and oxysterol levels. Among patients without target vessel failure, 46 out of 89 patients (52%) in the S arm and 34 out of 96 patients (35%) in the E+S arm were found to have coronary endothelial dysfunction (P=0.0256), and the incidence of target vessel dysfunction at follow-up was significantly decreased in the E+S arm (69/112 (62%) in S versus 47/109 (43%) in E+S; P=0.0059). A post hoc analysis of post-treatment low-density lipoprotein cholesterol-matched subgroups revealed that the incidence of both target vessel dysfunction and coronary endothelial dysfunction significantly decreased in the E+S arm, with significant reductions in oxysterol levels.

CONCLUSIONS:The CuVIC trial (Effect of Cholesterol Absorption Inhibitor Usage on Target Vessel Dysfunction after Coronary Stenting) has shown that ezetimibe with statins, compared with statin monotherapy, improves functional prognoses, ameliorating endothelial dysfunction in stented coronary arteries, and was associated with larger decreases in oxysterol levels..
3. Shunsuke Katsuki, Tetsuya Matoba, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Atherosclerotic Plaque Destabilization/Rupture in Mice by Regulating the Recruitment of Inflammatory Monocytes, CIRCULATION, 10.1161/CIRCULATIONAHA.113.002870, 129, 8, 896-906, 2014.02, Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture.
We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2(+/+)Ly-6C(high) inflammatory macrophages, but not CCR2(-/-) leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G(-)CD11b(+) monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture.
The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model..
4. Tetsuya Matoba, Kensuke Egashira, Anti-inflammatory gene therapy for cardiovascular disease., Curr Gene Ther, 11, 6, 442-446, 2011.12, [URL], Inflammation in the vascular wall is an essential hallmark during the development of atherosclerosis, for which major leukocytes infiltrated in the lesions are monocytes/macrophages. Therefore, monocyte chemoattractant protein-1 (MCP-1) and its primary receptor CC chemokine receptor 2 (CCR2) are feasible molecular targets for gene therapy to inhibit monocyte/macrophage-mediated inflammation in atherogenesis. A mutant MCP-1 that lacks N-terminal 7 amino acids (7ND) has been shown to heterodimerize with native MCP-1, bind to CCR2 and block MCP-1-mediated monocyte chemotaxis by a dominant-negative manner. Gene therapy using intramuscular transfection with plasmid DNA encoding 7ND showed inhibitory effects on atherosclerosis in hypercholesterolemic mice, and neointima formation after vascular injury in animal models. Bare metal stents for coronary intervention were coated with multiple thin layers of biocompatible polymer with 7ND plasmid. The 7ND gene-eluting stent inhibited macrophage infiltration surrounding stent struts and in-stent neointima formation in rabbit femoral arteries and cynomolgus monkey iliac arteries. Finally, the authors describe new application of 7ND plasmid encapsulated in polymer nanoparticle (NP) that functions as gene delivery system with unique in vivo kinetics. NP-mediated 7ND gene delivery inhibited MCP-1-induced chemotaxis of mouse peritoneal macrophage ex vivo, which may be applicable for the treatment of atherosclerotic cardiovascular disease. In conclusion, anti-inflammatory gene therapy targeting MCP-1/CCR2 signal, with a novel NP-mediated gene delivery system, is a potent therapeutic strategy for the treatment of cardiovascular diseases..
Presentations
1. Tetsuya Matoba, Kazuo Sakamoto, Masahiro Mohri, Yasuyuki Tsujita, Masao Yamasaki, Yasushi Ueki, Nobuhiro Tanaka, Yohei Hokama, Motoki Fukutomi, Katsutaka Hashiba, Rei Fukuhara, Yasushi Ueki, Satoru Suwa, Hirohide Matsuura, Eizo Tachibana, Takahiro Nakashima, Hayato Hosoda, Yoshio Tahara, Michikazu Nakai, Kunihiro Nishimura, Naohiro Yonemoto, Ken Nagao, The Impact of Institutional Characteristics on the Prognosis of Acute Myocardial Infarction with Cardiogenic Shock: Analysis from the JROAD/JROAD-DPC, 日本循環器学会学術集会, 2018.06.
Membership in Academic Society
  • Japanese Atherosclerosis Society
  • Japanese Heart Rhythm Society
  • The Japanese Vascular and Medicine Organization
  • American Heart Association
  • Japanese Association of Cardiovascular Intervention and Therapeutics
  • The Japanese Circulation Sciety
  • The Japanese Society of Internal Medicine
Awards
  • Identification of Hydrogen Peroxide as an Endothelium-Derived Hyperpolarizing Factor in Animals and Humans
Educational
Educational Activities
Education for medical students: Bedside teaching for grade 5, Clinical clerkship for grade 6
Education for graduate students: Basic and clinical research on cardiology and vascular biology
Education for medical staff in the university hospital on resuscitation and cardiovascular care
Social
Professional and Outreach Activities
Certified Instructor for American Heart Association BLS and ACLS Provider Course.