| Tetsuya Matoba | Last modified date：2023.12.06 |
Lecturer /
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences /
Angiocardiology /
Kyushu University Hospital
Reports
| 1. | Matoba Tetsuya, Shimokawa Hiroaki, Morikawa Keiko, Kubota Hiroshi, Fujiki Takako, Takeshita Akira, Possible involvement of Cu/Zn-SOD in the synthesis of endothelium-derived hyperpolarizing factor (EDHF) in mice, Circulation journal : official journal of the Japanese Circulation Society, Vol.66, p.192, 2002.03. |
| 2. | Morikawa Keiko, Shimokawa Hiroaki, Fujiki Takako, Kubota Hiroshi, Matoba Tetsuya, Hassan Talukder M.A., Hirakawa Yoji, Takeshita Akira, Influence of Diabetes Mellitus, Hypercholesterolemia, or Their Combination on Endothelium-Derived Hyperpolarizing Factor (EDHF)-Mediated Relaxations in Mice, Circulation journal : official journal of the Japanese Circulation Society, Vol.67, p.138, 2003.03. |
| 3. | Morikawa Keiko, Shimokawa Hiroaki, Matoba Tetsuya, Kubota Hiroshi, Fujiki Takako, Hassan Talukder M.A., Hirakawa Yoji, Takeshita Akira, Important Role of Cu/Zn-SOD in the Synthesis of Endothelium-Derived Hyperpolarizing Factor (EDHF) in Mice, Circulation journal : official journal of the Japanese Circulation Society, Vol.67, p.138, 2003.03. |
| 4. | Morikawa Keiko, Matoba Tetsuya, Kubota Hiroshi, Hatanaka Makoto, Fujiki Takako, Hassan Talukder M. A, Shimokawa Hiroaki, FRS-079 Endothelial Cu,Zn-SOD Plays a Pivotal Role in Endothelium-Dependent Hyperpolarization in Mice(NO and Cardiovascular System (H) : FRS10)(Featured Research Session (English)), Circulation journal : official journal of the Japanese Circulation Society, Vol.68, p.110, 2004.03. |
| 5. | Yasuhiro Nakano, Tetsuya Matoba, Yusaku Nagatomo, Hiroyuki Tsutsui, Percutaneous coil embolization and stent implantation for multiple coronary-to-pulmonary artery fistulas with giant coronary aneurysms: a case report., European heart journal. Case reports, 10.1093/ehjcr/ytac104, Vol.6, No.3, p.ytac104, 2022.03, Background: Multiple coronary-to-pulmonary artery fistulas (CPAFs) with giant coronary aneurysms (CAs) are extremely rare. The appropriate therapeutic indication and strategy for CPAFs have not been established. Case summary: Herein, we report the case of an asymptomatic 74-year-old woman with multiple CPAFs associated with giant CAs that had gradually developed over a 4-year period. After heart team discussion, we were successfully treated by minimally invasive intervention using transcatheter coil embolization and coronary stent implantation to prevent ruptures. Discussion: Coronary-to-pulmonary artery fistulas required evaluation of the appropriate timing of therapy initiation with reference to the presence of symptoms and fistula and aneurysm sizes, and determination of the optimal therapeutic approach with reference to the anatomy of the fistula with aneurysm and patient background characteristics.. |
| 6. | Nomura, Osamu Hashiba, Katsutaka Kikuchi, Migaku Kojima, Sunao Hanada, Hiroyuki Mano, Toshiaki Yamamoto, Takeshi Nakashima, Takahiro Tanaka, Akihito Nakayama, Naoki Yamaguchi, Junichi Matsuo, Kunihiro Matoba, Tetsuya Tahara, Yoshio Nonogi, Hiroshi, Performance of the 0-Hour/1-Hour Algorithm for Diagnosing Myocardial Infarction in Patients With Chest Pain in the Emergency Department ― A Systematic Review and Meta-Analysis ―, Circulation Reports, 10.1253/circrep.CR-22-0001, 2022.01. |
| 7. | Nakashima, Takahiro Hashiba, Katsutaka Kikuchi, Migaku Yamaguchi, Junichi Kojima, Sunao Hanada, Hiroyuki Mano, Toshiaki Yamamoto, Takeshi Tanaka, Akihito Matsuo, Kunihiro Nakayama, Naoki Nomura, Osamu Matoba, Tetsuya Tahara, Yoshio Nonogi, Hiroshi, Impact of Prehospital 12-Lead Electrocardiography and Destination Hospital Notification on Mortality in Patients With Chest Pain ― A Systematic Review ―, Circulation Reports, 10.1253/circrep.CR-22-0003, 2022.01. |
| 8. | Yamaguchi, Junichi Matoba, Tetsuya Kikuchi, Migaku Minami, Yuichiro Kojima, Sunao Hanada, Hiroyuki Mano, Toshiaki Nakashima, Takahiro Hashiba, Katsutaka Yamamoto, Takeshi Tanaka, Akihito Matsuo, Kunihiro Nakayama, Naoki Nomura, Osamu Tahara, Yoshio Nonogi, Hiroshi, Effects of Door-In to Door-Out Time on Mortality Among ST-Segment Elevation Myocardial Infarction Patients Transferred for Primary Percutaneous Coronary Intervention ― Systematic Review and Meta-Analysis ―, Circulation Reports, 10.1253/circrep.CR-21-0160, 2021.12. |
| 9. | Unexpected, but reasonable association between anderson-fabry disease and coronary vasospasm. |
| 10. | 的場 哲哉, 坂本 和生, 立花 栄三, 米本 直裕, 長尾 建, 心原性ショックを伴う急性心筋梗塞の予後に施設特徴が及ぼす影響 JROAD/JROAD-DPCの分析(The impact of institutional characteristics on the prognosis of acute myocardial infarction with cardiogenic shock: Analysis from the JROAD/JROAD-DPC), J-ReSS, Vol.11, p.31, 2018.04. |
| 11. | Shunsuke Katsuki, Tetsuya Matoba, Jun Ichiro Koga, Kaku Nakano, Kensuke Egashira, Anti-inflammatory Nanomedicine for Cardiovascular Disease, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2017.00087, Vol.4, 2017.12, Coronary artery disease, in the development of which inflammation mediated by innate immune cells plays a critical role, is one of the leading causes of death worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are a widely used lipid-lowering drug that has lipid-independent vasculoprotective effects, such as improvement of endothelial dysfunction, antioxidant properties, and inhibitory effects on inflammation. Despite recent advances in lipid-lowering therapy, clinical trials of statins suggest that anti-inflammatory therapy beyond lipid-lowering therapy is indispensible to further reduce cardiovascular events. One possible therapeutic option to the residual risk is to directly intervene in the inflammatory process by utilizing a nanotechnology-based drug delivery system (nano-DDS). Various nano-sized materials are currently developed as DDS, including micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and metallic nanoparticles. The application of nano-DDS to coronary artery disease is a feasible strategy since the inflammatory milieu enhances incorporation of nano-sized materials into mononuclear phagocytic system and permeability of target lesions, which confers nano-DDS on “passive-targeting” property. Recently, we have developed a polymeric nanoparticle-incorporating statin to maximize its anti-inflammatory property. This statin nanoparticle has been tested in various disease models, including plaque destabilization and rupture, myocardial ischemia-reperfusion injury, and ventricular remodeling after acute myocardial infarction, and its clinical application is in progress. In this review, we present current development of DDS and future perspective on the application of anti-inflammatory nanomedicine to treat life-threatening cardiovascular diseases.. |
| 12. | Matoba T, Koga J-I, Nakano K, Egashira K, Tsutsui H, Nanoparticle-mediated drug delivery system for atherosclerotic cardiovascular disease., J Cardiol, 10.1016/j.jjcc.2017.03.005, 2017.09, [URL], Administration of drugs and other therapeutic agents has been the central strategy of contemporary medicine for cardiovascular disease. The use of drug delivery systems (DDS) includes micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and crystalline metals. Nano-DDS modify in vivo drug kinetics, depending on (patho)physiological mechanisms such as retard excretion, vascular permeability, and incorporation by mononuclear phagocyte systems, which constitute the 'passive-targeting' property of nano-DDS. These properties of nano-DDS are applicable to inflammatory diseases including atherosclerosis. Atherosclerotic plaque destabilization and rupture account for the majority of acute myocardial infarction, for which inflammatory monocytes and macrophages play critical roles. In our experience, polymeric nanoparticles have been delivered to inflammatory monocytes and macrophages in an atherosclerotic mouse model. Nano-DDS loaded with pioglitazone reduced Ly6C(high) inflammatory monocytes and increased Ly6C(low) non-inflammatory monocytes in the peripheral blood, and induced M2 macrophage-associated genes in the aorta. Pioglitazone-nanoparticles finally stabilized atherosclerotic plaques assessed by a decrease in the number of buried fibrous caps in the plaque. Application of nano-DDS is a unique and promising approach to prevent life-threatening cardiovascular events including acute myocardial infarction by regulating inflammation in the cardiovascular system.. |
| 13. | Tetsuya Matoba, Susumu Takase, Response by Takase and Matoba to Letter Regarding Article, "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"., 2017.05, [URL]. |
| 14. | Susumu Takase, Tetsuya Matoba, Response by Takase and Matoba to Letter Regarding Article, "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.117.309301, Vol.37, No.5, p.E54, 2017.05. |
| 15. | Tetsuya Matoba, Katsuya Honda, Jun-ichiro Koga, Kaku Nakano, Hiroyuki Tsutsui, Kensuke Egashira, Statin and Ezetimibe Differently Affect Spontaneous Atherothrombotic Occlusion in a Rabbit Model of Plaque Erosion, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol.37, 2017.05. |
| 16. | Tetsuya Matoba, Jun-ichiro Koga, Kaku Nakano, Egashira kensuke, Hiroyuki Tsutsui, Nanoparticle-mediated drug delivery system for atherosclerotic cardiovascular disease, Journal of Cardiology, 10.1016/j.jjcc.2017.03.005, 2017.04, [URL]. |
| 17. | Ken Onitsuka, Masahiro Mohri, Yasushi Ueki, Satoru Suwa, Hiroshi Takahashi, Yohei Hokama, Nobuhiro Tanaka, Toshiaki Kadokami, Tetsuya Matoba, Rei Fukuhara, Tsukasa Yagi, Eizo Tachibana, Naohiro Yonemoto, Ken Nagao, CLINICAL CHARACTERISTICS AND IN-HOSPITAL MORTALITY OF VERY ELDERLY PATIENTS WITH CARDIOVASCULAR SHOCK IN JAPAN: THE RESULTS FROM JAPANESE CIRCULATION SOCIETY SHOCK REGISTRY, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol.69, No.11, p.293, 2017.03. |
| 18. | Shunsuke Katsuki, Tetsuya Matoba, Jun-Ichiro Koga, Kaku Nakano, Kensuke Egashira, Anti-inflammatory Nanomedicine for Cardiovascular Disease, Frontiers in cardiovascular medicine, 10.3389/fcvm.2017.00087, 2017, Coronary artery disease, in the development of which inflammation mediated by innate immune cells plays a critical role, is one of the leading causes of death worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are a widely used lipid-lowering drug that has lipid-independent vasculoprotective effects, such as improvement of endothelial dysfunction, antioxidant properties, and inhibitory effects on inflammation. Despite recent advances in lipid-lowering therapy, clinical trials of statins suggest that anti-inflammatory therapy beyond lipid-lowering therapy is indispensible to further reduce cardiovascular events. One possible therapeutic option to the residual risk is to directly intervene in the inflammatory process by utilizing a nanotechnology-based drug delivery system (nano-DDS). Various nano-sized materials are currently developed as DDS, including micelles, liposomes, polymeric nanoparticles, dendrimers, carbon nanotubes, and metallic nanoparticles. The application of nano-DDS to coronary artery disease is a feasible strategy since the inflammatory milieu enhances incorporation of nano-sized materials into mononuclear phagocytic system and permeability of target lesions, which confers nano-DDS on "passive-targeting" property. Recently, we have developed a polymeric nanoparticle-incorporating statin to maximize its anti-inflammatory property. This statin nanoparticle has been tested in various disease models, including plaque destabilization and rupture, myocardial ischemia-reperfusion injury, and ventricular remodeling after acute myocardial infarction, and its clinical application is in progress. In this review, we present current development of DDS and future perspective on the application of anti-inflammatory nanomedicine to treat life-threatening cardiovascular diseases.. |
| 19. | Koshin Horimoto, Kohtaro Abe, Kisho Ohtani, Yusuke Takahara, Kazuya Hosokawa, Keiji Oi, Yasushi Mukai, Takashi Kubo, Tetsuya Matoba, Hiroyuki Tsutsui, Optical Frequency Domain Imaging of Covered Stent-Graft for Pulmonary Artery Pseudoaneurysm After Balloon Pulmonary Angioplasty, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2016.08.022, Vol.9, No.21, pp.2255-2256, 2016.11. |
| 20. | Nanoparticle-mediated drug delivery system for acute myocardial infarction. |
| 21. | Kenzo Ichimura, Tetsuya Matoba, Kaku Nakano, Masaki Tokutome, Jyunichiro Koga, Kensuke Egashira, Nanoparticle-Mediated Targeting of Pitavastatin into Small Pulmonary Arteries by Intravenous Administration Attenuates the Progression of Monocrotaline-Induced Pulmonary Hypertension in Rats, JOURNAL OF CARDIAC FAILURE, Vol.22, No.9, p.S199, 2016.09. |
| 22. | Masaki Tokutome, Tetsuya Matoba, Yasuhiro Nakano, Kaku Nakano, Kensuke Egashira, Nanoparticles-Mediated Targeting of Pioglitazone Reduces Myocardial Ischemia-Reperfusion Injury and Cardiac Remodeling by Antagonizing Monocyte/Macrophage-mediated Inflammation in Preclinical Animal Models, JOURNAL OF CARDIAC FAILURE, Vol.22, No.9, p.S213, 2016.09. |
| 23. | K. Ichimura, T. Matoba, K. Nakano, K. Egashira, Nanoparticle-mediated targeting of pitavastatin into small pulmonary arteries by intravenous administration attenuates the progression of monocrotaline-induced pulmonary arterial hypertension in rats, EUROPEAN HEART JOURNAL, Vol.37, p.397, 2016.08. |
| 24. | G. Ikeda, T. Matoba, A. Ishikita, K. Nakano, K. Egashira, Novel nanoparticle-mediated medicine for myocardial ischemia-reperfusion injury simultaneously targeting mitochondrial injury and myocardial inflammation, EUROPEAN HEART JOURNAL, Vol.37, p.822, 2016.08. |
| 25. | 的場 哲哉, 坂本 和生, 毛利 正博, 田中 信大, 外間 洋平, 福冨 基城, 羽柴 克孝, 福原 怜, 植木 康志, 諏訪 哲, 松浦 広英, 立花 栄三, 米本 直裕, 長尾 健, JCSショックレジストリ学術委員会, 心原性ショックを受けた急性冠動脈症候群患者における血行再建の予後に対する影響 JCSショック医療統計の分析(Prognostic Impact of Coronary Revascularization in Acute Coronary Syndrome Patients with Cardiogenic Shock: Analysis from the JCS Shock registry), 日本心血管インターベンション治療学会抄録集, Vol.25回, pp.LB02-8, 2016.07. |
| 26. | Tetsuya Matoba, Knowing the Risks of the Vessels From the Vessels, CIRCULATION JOURNAL, 10.1253/circj.CJ-16-0164, Vol.80, No.4, pp.825-826, 2016.04. |
| 27. | Gentaro Ikeda, Tetsuya Matoba, Kensuke Egashira, Nanoparticle-mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-reperfusion Injury, CIRCULATION, Vol.132, 2015.11. |
| 28. | Nanoparticle-mediated Drug Delivery System for Acute Myocardial Infarction. |
| 29. | Gentaro Ikeda, Tetsuya Matoba, Ayako Ishikita, Kensuke Egashira, Nanoparticle-mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-reperfusion Injury, CIRCULATION RESEARCH, Vol.117, 2015.07. |
| 30. | Satoshi Akagi, Kazufumi Nakamura, Daiji Miura, Yukihiro Saito, Hiromi Matsubara, Aiko Ogawa, Tetsuya Matoba, Kensuke Egashira, Hiroshi Ito, Delivery of Imatinib-Incorporated Nanoparticles into Lungs Suppresses the Development of Monocrotaline-Induced Ulmonary Arterial Hypertension, International Heart Journal, 10.1536/ihj.14-338, Vol.56, No.3, pp.354-359, 2015.04, Platelet–derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by 3H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PASMCs.. |
| 31. | Gentaro Ikeda, Tetsuya Matoba, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Simultaneous Targeting to Mitochondria and Inflammatory Monocytes Confers Additive Cardioprotection Against Myocardial Ischemia-Reperfusion Injury, CIRCULATION, Vol.130, 2014.11. |
| 32. | Kenzo Ichimura, Tetsuya Matoba, Ryoji Nagahama, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pitavastatin into Small Pulmonary Arteies by Intravenous Administration Attenuated the Progression of Already Established Monocrotaline-induced Pulmonary Arterial Hypertension in Rats, CIRCULATION, Vol.130, 2014.11. |
| 33. | Ayako Ishikita, Tetsuya Matoba, Gentaro Ikeda, Yajing Mao, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Targeting of a Mitochondria Division Inhibitor, Mdivi-1, to the Mitochondria Induces Cardioprotection from Ischemia-Reperfusion Injury, CIRCULATION, Vol.130, 2014.11. |
| 34. | Soichi Nakashiro, Tetsuya Matoba, Jun-ichiro Koga, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-mediated Delivery of Pioglitazone Ameliorates Inflammation and Inhibits Atherosclerotic Plaque Rupture in Apolipoprotein-E Deficient Mice, CIRCULATION, Vol.130, 2014.11. |
| 35. | Masaki Tokutome, Tetsuya Matoba, Yasuhiro Nakano, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticles-Mediated Delivery of Pioglitazone Reduces Myocardial Ischemia-Reperfusion Injury by Antagonizing Monocyte-mediated Inflammation in Mice and Mini Pigs, CIRCULATION, Vol.130, 2014.11. |
| 36. | K. Ichimura, T. Matoba, K. Nakano, K. Nagaoka, K. Sunagawa, K. Egashira, Nanoparticle-mediated targeting of pitavastatin into reperfused myocardium reduces ischemia-reperfusion injury in a preclinical pig model, EUROPEAN HEART JOURNAL, Vol.35, p.443, 2014.09. |
| 37. | G. Ikeda, T. Matoba, Y. Nakano, K. Nagaoka, K. Nakano, K. Sunagawa, K. Egashira, Nanoparticle-mediated targeting of cyclosporine a to the mitochondria of reperfused myocardium enhances cardioprotection against ischemia-reperfusion injury in preclinical models, EUROPEAN HEART JOURNAL, Vol.35, p.6, 2014.09. |
| 38. | Tetsuya Matoba, Egashira kensuke, Nanoparticle-Mediated Drug Delivery System for Cardiovascular Disease, 2014.08, [URL], Administration of drugs and other therapeutic agents has been the central strategy of contemporary medicine for cardiovascular disease. The use of a drug delivery system (DDS) is always demanded to enhance the efficacy and safety of therapeutic agents, and improve the signal-to-noise ratio of imaging agents. Nano-scale materials modify in vivo drug kinetics, depending on (patho)physiological mechanisms such as vascular permeability and incorporation by the mono- nuclear phagocyte system, which constitute ‘passive-targeting’ properties of nano-DDS. By contrast, an ‘active-target- ing’ strategy employs a specific targeting structure on nano-DDS, which binds to the target molecule that is specific for a certain disease process, such as tumor specific antigens and the induction of adhesion molecules. In this review, we sum- marize recent studies that applied nano-DDS for the diagnosis and treatment of cardiovascular disease, especially focus- ing on atherosclerosis and myocardial ischemia-reperfusion (IR) injury. Pathophysiological changes in atherosclerosis and myocardial IR injury are successfully targeted by nano-DDS and preclinical studies in animals showed positive ef- fects of nano-DDS enhancing efficacy and reducing adverse effects. The development of nano-DDS in clinical medicine iskeenlybeingawaited.. |
| 39. | Shunsuke Katsuki, Tetsuya Matoba, Soichi Nakashiro, Kei Sato, Jun-ichiro Koga, Kaku Nakano, Yasuhiro Nakano, Shizuka Egusa, 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, Vol.129, No.8, pp.896-906, 2014.02, BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.. |
| 40. | Tetsuya Matoba, Kensuke Egashira, Nanoparticle-mediated drug delivery system for cardiovascular disease, International heart journal, 10.1536/ihj.14-150, 2014.01, Administration of drugs and other therapeutic agents has been the central strategy of contemporary medicine for cardiovascular disease. The use of a drug delivery system (DDS) is always demanded to enhance the efficacy and safety of therapeutic agents, and improve the signal-to-noise ratio of imaging agents. Nano-scale materials modify in vivo drug kinetics, depending on (patho)physiological mechanisms such as vascular permeability and incorporation by the mononuclear phagocyte system, which constitute 'passive-targeting' properties of nano-DDS. By contrast, an 'active-targeting' strategy employs a specific targeting structure on nano-DDS, which binds to the target molecule that is specific for a certain disease process, such as tumor specific antigens and the induction of adhesion molecules. In this review, we summarize recent studies that applied nano-DDS for the diagnosis and treatment of cardiovascular disease, especially focusing on atherosclerosis and myocardial ischemia-reperfusion (IR) injury. Pathophysiological changes in atherosclerosis and myocardial IR injury are successfully targeted by nano-DDS and preclinical studies in animals showed positive effects of nano-DDS enhancing efficacy and reducing adverse effects. The development of nano-DDS in clinical medicine is keenly being awaited.. |
| 41. | Yoshibumi Antoku, Tetsuya Matoba, Takeo Yufu, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, A Novel Rabbit Model of Plaque Erosion With Spontaneous Atherothrombotic Occlusion, CIRCULATION, Vol.128, No.22, 2013.11. |
| 42. | Ken Nagao, Hiroshi Nonogi, Naohiro Yonemoto, Singo Furuya, Sigemasa Tani, Naoya Matumoto, Morimasa Talcayama, Shinichi Shirai, Takeshi Kimura, Choukou Genka, Eizo Tachibana, Hiromi Seo, Hideharu Tanaka, Hiromi Seo, Hiroyuki Yokoyama, Kazuo Kimura, Keijiro Saku, Kunio Oota, Mamoru Hase, Migaku Kikuchi, Naoki Shimizu, Satoshi Takeda, Shigeru Kanesaka, Sunao Kojima, Takanori Ikeda, Taku Iwami, Tetsuya Matoba, Toshiaki Mano, Tetsuhisa Kitamura, Yoshihiko Seino, Yoshio Tahara, Chest-Compression-Only Bystander Cardiopulmonary Resuscitation in the 30:2 Compression-to-Ventilation Ratio Era - Nationwide Observational Study -, CIRCULATION JOURNAL, 10.1253/circj.CJ-13-0457, Vol.77, No.11, pp.2742-2750, 2013.11, Background: The compression-to-ventilation ratio for basic cardiopulmonary resuscitation (CPR) was changed from 15:2 to 30:2, but there are few human studies comparing chest-compression-only CPR with standard CPR.Methods and Results: From the All-Japan Utstein Registry in the 30:2 CPR era, 173,565 adult cardiac arrests witnessed by bystanders were included. On arrival at the scene, emergency medical services responders assessed the status of dispatcher-assisted CPR instruction and bystander CPR technique (chest compression with or without rescue breathing). The primary endpoint was favorable neurological outcome 30 days after cardiac arrest. The prevalence of dispatcher-assisted CPR instruction increased year by year, contributing to an overall increase of chest-compression-only bystander CPR from 20.6% to 35.0%. Among 78,150 patients receiving bystander CPR, favorable neurological outcome did not differ between dispatcher-assisted and -unassisted CPR (adjusted odds ratio [OR], 1.00; 95% confidence interval [CI]: 0.94-1.08). Chest-compression-only CPR resulted in better favorable neurological outcome than standard CPR in the whole cohort (adjusted OR, 1.09; 95% CI: 1.00-1.18) and in the subgroup with cardiac etiology (adjusted OR, 1.12; 95% CI: 1.02-1.22). The addition of rescue breathing provided no neurological benefit in the non-cardiac etiology subgroup.Conclusions: In the 30:2 CPR era, dispatcher-assisted CPR instruction contributed to an increase of chest-compression-only bystander CPR, supporting the use of chest-compression-only CPR for bystander-witnessed out-of-hospital cardiac arrest in all adults.. |
| 43. | Kenzo Ichimura, Kaku Nakano, Kazuhiro Nagaoka, Tetsuya Matoba, Shizuka Egusa, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Targeting of Pitavastatin Into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Pig Model, CIRCULATION, Vol.128, No.22, 2013.11. |
| 44. | Tetsuya Matoba, Kei Sato, Kensuke Egashira, Mouse models of plaque rupture, CURRENT OPINION IN LIPIDOLOGY, 10.1097/MOL.0b013e3283646e4d, Vol.24, No.5, pp.419-425, 2013.10, Purpose of reviewAtherosclerotic plaque destabilization and rupture is an important pathological condition that may account for approximately 70% of acute myocardial infarction cases. To analyse the mechanisms by which an atherosclerotic plaque destabilizes and ruptures and examine the effects of novel therapeutic approaches, several groups have developed mouse models of plaque rupture.Recent findingsFindings from intracoronary imaging modalities support the role of rupture-prone vulnerable plaques' characterized by pathological studies as precursors of plaque rupture and acute myocardial infarction. Atherosclerotic plaques in the brachiocephalic arteries of apolipoprotein E (ApoE)-deficient mice fed a high-fat diet demonstrate several key histological features of ruptured human plaques. Angiotensin II infusion accelerates plaque destabilization and rupture, which has enabled researchers to analyse the role of pathophysiological and genetic factors that accelerate plaque destabilization and rupture and qualitatively examine the effects of experimental therapies. The plaque rupture model in the brachiocephalic arteries of ApoE-deficient mice is disputed due to dissimilarities from human plaques regarding the incidence of thrombotic occlusion and computer-simulated mechanical stress in the plaque.SummaryAlthough no mouse model examined completely simulates the entire process of plaque rupture, the brachiocephalic artery in ApoE-deficient mice fed a high-fat diet, with or without angiotensin II infusion, is a practically feasible model for plaque rupture.. |
| 45. | Kazuhiro Nagaoka, Tetsuya Matoba, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, A New Therapeutic Modality for Ischemia-Reperfusion Injury: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia/Reperfusion Injury in Rats, CIRCULATION, Vol.126, No.21, 2012.11. |
| 46. | Yasuhiro Nakano, Tetsuya Matoba, Gentaro Ikeda, Kazuhiro Nagaoka, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, A Novel Multi-Targeting Approach for Myocardial Ischemia-Reperfusion Injury: Nanoparticle-Mediated Delivery of Irbesartan Reduces Ischemia/Reperfusion Injury in Mice, CIRCULATION, Vol.126, No.21, 2012.11. |
| 47. | Yoshibumi Antoku, Tetsuya Matoba, Takeo Yufu, Kaku Nakano, Kensuke Egashira, An Unique Animal Model of Spontaneous Atherothrombotic Occlusion due to Plaque Erosion at Femoral Arteries of Atherosclerotic Rabbits Infused with Angiotension II, CIRCULATION, Vol.126, No.21, 2012.11. |
| 48. | Shunsuke Katsuki, Tetsuya Matoba, Kei Sato, Jun-ichiro Koga, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Plaque Destabilization and Rupture in the Brachiocephalic Arteries of ApoE-Deficient Mice through Regulating Monocyte Activation, CIRCULATION, Vol.126, No.21, 2012.11. |
| 49. | Ryoji Nagahama, Tetsuya Matoba, Kaku Nakano, Shokei Kim-Mitsuyama, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-mediated delivery of pioglitazone enhances therapeutic neovascularization in a murine model of hindlimb ischemia., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/ATVBAHA.112.253823, Vol.32, No.10, pp.2427-34, 2012.10, OBJECTIVE: Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator-activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model. METHODS AND RESULTS: In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin-positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase-deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP. CONCLUSIONS: NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery disease with critical limb ischemia.. |
| 50. | Tetsuya Matoba, Kensuke Egashira, Anti-Inflammatory Gene Therapy for Cardiovascular Disease, CURRENT GENE THERAPY, 10.2174/156652311798192888, Vol.11, No.6, pp.442-446, 2011.12, 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.. |
| 51. | Kazuhiro Nagaoka, Tetsuya Matoba, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, A New Therapeutic Modality for Ischemia-Reperfusion Injury: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Myocardial Ischemia/Reperfusion Injury in Rats, CIRCULATION, Vol.124, No.21, 2011.11. |
| 52. | Tetsuya Matoba, Masao Takemoto, Susumu Takase, Shinobu Arai, Yasushi Mukai, Shujiro Inoue, Taiki Higo, James K. Liao, Kensuke Egashira, Kenji Sunagawa, Intensive Lipid-Lowering Therapy by Pitavastatin Ameliorates Coronary Hypercontraction After Stenting, the CONTRACTION Study, CIRCULATION, Vol.124, No.21, 2011.11. |
| 53. | Plaque destabilization and inflammation. |
| 54. | Ling Chen, Kaku Nakano, Satoshi Kimura, Tetsuya Matoba, Eiko Iwata, Miho Miyagawa, Hiroyuki Tsujimoto, Kazuhiro Nagaoka, Junji Kishimoto, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-mediated delivery of pitavastatin into lungs ameliorates the development and induces regression of monocrotaline-induced pulmonary artery hypertension., Hypertension (Dallas, Tex. : 1979), 10.1161/HYPERTENSIONAHA.110.157032, Vol.57, No.2, pp.343-50, 2011.02, Pulmonary artery hypertension (PAH) is an intractable disease of the small PAs in which multiple pathogenic factors are involved. Statins are known to mitigate endothelial injury and inhibit vascular remodeling and inflammation, all of which play crucial roles in the pathogenesis of PAH. We tested the hypothesis that nanoparticle (NP)-mediated delivery of pitavastatin into the lungs can be a novel therapeutic approach for the treatment of PAH. Among the marketed statins, pitavastatin was found to have the most potent effects on proliferation of PA smooth muscle cells in vitro. We formulated pitavastatin-NP and found that pitavastatin-NP was more effective than pitavastatin alone in inhibiting cellular proliferation and inflammation in vitro. In a rat model of monocrotaline-induced PAH, a single intratracheal instillation of NP resulted in the delivery of NP into alveolar macrophages and small PAs for up to 14 days after instillation. Intratracheal treatment with pitavastatin-NP, but not with pitavastatin, attenuated the development of PAH and was associated with a reduction of inflammation and PA remodeling. NP-mediated pitavastatin delivery was more effective than systemic administration of pitavastatin in attenuating the development of PAH. Importantly, treatment with pitavastatin-NP 3 weeks after monocrotaline injection induced regression of PAH and improved survival rate. This mode of NP-mediated pitavastatin delivery into the lungs is effective in attenuating the development of PAH and inducing regression of established PAH, suggesting potential clinical significance for developing a new treatment for PAH.. |
| 55. | Kei Sato, Tetsuya Matoba, Shunsuke Katsuki, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, NPC1L1 Inhibition with Ezetimibe Prevents Accelerated Plaque Destabilization and Rupture Induced by Dietary Cholesterol Oxidation Products in ApoE-deficient Mice, CIRCULATION, Vol.122, No.21, 2010.11. |
| 56. | Kei Sato, Tetsuya Matoba, Shunsuke Katsuki, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, NPC1L1 Inhibition with Ezetimibe Suppresses Enhanced Formation of Aortic Atherosclerosis Induced by Dietary Cholesterol Oxidation Products in ApoE-deficient Mice, CIRCULATION, Vol.122, No.21, 2010.11. |
| 57. | Shunsuke Katsuki, Tetsuya Matoba, Kaku Nakano, Kei Sato, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Monocyte-Selective Delivery of Pitavastatin Inhibits Monocyte Activation and Attenuates Plaque Destabilization and Rupture in ApoE-Deficient Mice, CIRCULATION, Vol.122, No.21, 2010.11. |
| 58. | Shunsuke Katsuki, Tetsuya Matoba, Jun-ichiro Koga, Kaku Nakano, Kei Sato, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-Mediated Monocyte-Selective Delivery of Pitavastatin Prevents Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in ApoE-Deficient Mice, CIRCULATION, Vol.122, No.21, 2010.11. |
| 59. | Ryoji Nagahama, Tetsuya Matoba, Kaku Nakano, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-mediated Endothelial Cell-selective Delivery of Pioglitazone Enhances Therapeutic Efficacy of Therapeutic Angiogenesis and Arteriogenesis after Hindlimb Ischemia in Mice, CIRCULATION, Vol.122, No.21, 2010.11. |
| 60. | Shinichiro Oda, Ryoji Nagahama, Kaku Nakano, Tetsuya Matoba, Mitsuki Kubo, Kenji Sunagawa, Ryuji Tominaga, Kensuke Egashira, Nanoparticle-mediated endothelial cell-selective delivery of pitavastatin induces functional collateral arteries (therapeutic arteriogenesis) in a rabbit model of chronic hind limb ischemia, JOURNAL OF VASCULAR SURGERY, 10.1016/j.jvs.2010.03.020, Vol.52, No.2, pp.412-420, 2010.08, Objectives: We recently demonstrated in a murine model that nanoparticle-mediated delivery of pitavastatin into vascular endothelial cells effectively increased therapeutic neovascularization. For the development of a clinically applicable approach, further investigations are necessary to assess whether this novel system can induce the development of collateral arteries (arteriogenesis) in a chronic ischemia setting in larger animals. Methods: Chronic hind limb ischemia was induced in rabbits. They were administered single injections of nanoparticles loaded with pitavastatin (0.05, 0.15, and 0.5 mg/kg) into ischemic muscle. Results: Treatment with pitavastatin nanoparticles (0.5 mg/kg), but not other nanoparticles, induced angiographically visible arteriogenesis. The effects of intramuscular injections of phosphate-buffered saline, fluorescein isothiocyanate (FITC)-loaded nanoparticles, pitavastatin (0.5 mg/kg), or pitavastatin (0.5 mg/kg) nanoparticles were examined. FITC nanoparticles were detected mainly in endothelial cells of the ischemic muscles for up to 4 weeks. Treatment with pitavastatin nanoparticles, but not other treatments, induced therapeutic arteriogenesis and ameliorated exercise-induced ischemia, suggesting the development of functional collateral arteries. Pretreatment with nanoparticles loaded with vatalanib, a vascular endothelial growth factor receptor (VEGF) tyrosine kinase inhibitor, abrogated the therapeutic effects of pitavastatin nanoparticles. Separate experiments with mice deficient for VEGF receptor tyrosine kinase demonstrated a crucial role of VEGF receptor signals in the therapeutic angiogenic effects. Conclusions: The nanotechnology platform assessed in this study (nanoparticle-mediated endothelial cell-selective delivery of pitavastatin) may be developed as a clinically feasible and promising strategy for therapeutic arteriogenesis in patients. (J Vasc Surg 2010;52:412-20.). |
| 61. | Statins in the management of acute coronary syndrome HMG-CoA reductase inhibitors(statins) are widely used to treat dyslipidemia, and now play an important role in the management of acute coronary syndrome (ACS). Besides their lipid lowering effect, statins display 'pleiotropic effects' that include improvement of nitric oxide bioavailability, inhibition of inflammatory cytokine expression and inhibition of blood coagulability, which may ameliorate the pathogenesis of ACS as shown in animal models and human studies. In clinical trials, statins are proven to reduce the risk of ACS in primary as well as secondary prevention, in which LDL cholesterol lowering correlates with the risk reduction for ACS. Recent trials suggested that the immediate initiation of statins benefit the ACS patients reducing recurrent ischemic events and improve prognosis. These evidences suggest that more aggressive statin treatment may benefit both low- and high-risk patients in the management of ACS.. |
| 62. | Tetsuya Matoba, Masao Takemoto, Yasushi Mukai, Shujiro Inoue, Shinobu Kawamura-Arai, Kensuke Noma, Ryuji Okamoto, James K. Liao, Kenji Sunagawa, High Incidence of Coronary Vasospasm After Sirolimus-Eluting Stent Implantation: Role of Rho-associated Kinase Activation, CIRCULATION, Vol.120, No.18, p.S914, 2009.11. |
| 63. | Ryoji Nagahama, Tetsuya Matoba, Kaku Nakano, Kaori Hara, Hiroyuki Tsujimoto, Kenji Sunagawa, Kensuke Egashira, Nanoparticle-mediated Endothelial Cell-selective Delivery of Pioglitazone Improves Therapeutic Efficacy of Ischemic Neovascularization, CIRCULATION, Vol.120, No.18, p.S1151, 2009.11. |
| 64. | Takaharu Shirahama, Tetsuya Matoba, Ryoji Nagahama, Yamin Tian, Kaku Nakano, Hiroyuki Tsujimoto, Kenji Sunagawa, Kensuke Egashira, Ninoparticle-Mediated Delivery of Pioglitazone Effectively Attenuates Neointimal Formation After Wire Injury in Mice, CIRCULATION, Vol.120, No.18, p.S1172, 2009.11. |
| 65. | Noriaki Tsukie, Kensuke Egashira, Kaku Nakano, Tetsuya Matoba, Kenji Sunagawa, Pitavastatin Incorporated Nanoparticle-eluting Stents Attenuate In-stent Stenosis Without Anti-healing Effects Induced by Sirolimus-eluting Stents (cypher) in Porcine Coronary Artery Model, CIRCULATION, Vol.120, No.18, p.S951, 2009.11. |
| 66. | L. Chen, K. Nakano, S. Kimura, T. Matoba, K. Sunagawa, K. Egashira, Nanoparticle-mediated delivery of angiotensin II receptor antagonist, olmesartan medoxomil into lungs ameliorates monocrotaline-induced pulmonary arterial hypertension in rats, INTERNATIONAL JOURNAL OF CARDIOLOGY, 10.1016/j.ijcard.2009.09.500, Vol.137, p.S145, 2009.10. |
| 67. | Rotational atherectomy for calcified coronary stenosis in elderly patients with severe left ventricular dysfunction: Three case reports Rotational atherectomy (ROTA) is an effective modality of percutaneous coronary intervention (PCI) for calcified coronary stenoses. However, the manufacture dose not recommend the use of ROTA in patients with severe left ventricular (LV) dysfunction, especially with a LV ejection fraction of less than 30%. We experienced 3 elderly patients with severe LV dysfunction and an EF of less than 25%, who underwent ROTA for coronary calcified stenoses without any complications while taking appropriate measures before and during the PCI, and ultimately obtained excellent clinical courses.. |
| 68. | Kimio Satoh, Patrizia Nigro, Tetsuya Matoba, Michael R. O'Dell, Zhaoqiang Cui, Xi Shi, Amy Mohan, Chen Yan, Jun-ichi Abe, Karl A. Illig, Bradford C. Berk, Cyclophilin A enhances vascular oxidative stress and the development of angiotensin II-induced aortic aneurysms, NATURE MEDICINE, 10.1038/nm.1958, Vol.15, No.6, pp.649-U144, 2009.06, Inflammation and oxidative stress are pathogenic mediators of many diseases, but molecules that could be therapeutic targets remain elusive. Inflammation and matrix degradation in the vasculature are crucial for abdominal aortic aneurysm (AAA) formation. Cyclophilin A (CypA, encoded by Ppia) is highly expressed in vascular smooth muscle cells (VSMCs), is secreted in response to reactive oxygen species (ROS) and promotes inflammation. Using the angiotensin II (AngII)-induced AAA model in Apoe(-/-) mice, we show that Apoe(-/-) Ppia(-/-) mice are completely protected from AngII-induced AAA formation, in contrast to Apoe(-/-) Ppia(+/+) mice. Apoe(-/-) Ppia(-/-) mice show decreased inflammatory cytokine expression, elastic lamina degradation and aortic expansion. These features were not altered by reconstitution of bone marrow cells from Ppia(+/+) mice. Mechanistic studies showed that VSMC-derived intracellular and extracellular CypA are required for ROS generation and matrix metalloproteinase-2 activation. These data define a previously undescribed role for CypA in AAA formation and suggest CypA as a new target for treating cardiovascular disease.. |
| 69. | Mitsuki Kubo, Kensuke Egashira, Takahiro Inoue, Jun-ichiro Koga, Shinichiro Oda, Ling Chen, Kaku Nakano, Tetsuya Matoba, Yoshiaki Kawashima, Kaori Hara, Hiroyuki Tsujimoto, Katsuo Sueishi, Ryuji Tominaga, Kenji Sunagawa, Therapeutic Neovascularization by Nanotechnology-Mediated Cell-Selective Delivery of Pitavastatin Into the Vascular Endothelium, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 10.1161/ATVBAHA.108.182584, Vol.29, No.6, pp.796-U47, 2009.06, Objective-Recent clinical studies of therapeutic neovascularization using angiogenic growth factors demonstrated smaller therapeutic effects than those reported in animal experiments. We hypothesized that nanoparticle (NP)-mediated cell-selective delivery of statins to vascular endothelium would more effectively and integratively induce therapeutic neovascularization. Methods and Results-In a murine hindlimb ischemia model, intramuscular injection of biodegradable polymeric NP resulted in cell-selective delivery of NP into the capillary and arteriolar endothelium of ischemic muscles for up to 2 weeks postinjection. NP-mediated statin delivery significantly enhanced recovery of blood perfusion to the ischemic limb, increased angiogenesis and arteriogenesis, and promoted expression of the protein kinase Akt, endothelial nitric oxide synthase (eNOS), and angiogenic growth factors. These effects were blocked in mice administered a nitric oxide synthase inhibitor, or in eNOS-deficient mice. Conclusions-NP-mediated cell-selective statin delivery may be a more effective and integrative strategy for therapeutic neovascularization in patients with severe organ ischemia. (Arterioscler Thromb Vasc Biol. 2009; 29: 796-801.). |
| 70. | Kaku Nakano, Kensuke Egashira, Seigo Masuda, Kouta Funakoshi, Gang Zhao, Satoshi Kimura, Tetsuya Matoba, Katsuo Sueishi, Yasuhisa Endo, Yoshiaki Kawashima, Kaori Hara, Hiroyuki Tsujimoto, Ryuji Tominaga, Kenji Sunagawa, Formulation of Nanoparticle-Eluting Stents by a Cationic Electrodeposition Coating Technology Efficient Nano-Drug Delivery via Bioabsorbable Polymeric Nanoparticle-Eluting Stents in Porcine Coronary Arteries, JACC-CARDIOVASCULAR INTERVENTIONS, 10.1016/j.jcin.2008.08.023, Vol.2, No.4, pp.277-283, 2009.04, Objectives The objective of this study was to formulate a nanoparticle (NP)-eluting drug delivery stent system by a cationic electrodeposition coating technology. Background Nanoparticle-mediated drug delivery systems (DDS) are poised to transform the development of innovative therapeutic devices. Therefore, we hypothesized that a bioabsorbable polymeric NP-eluting stent provides an efficient DDS that shows better and more prolonged delivery compared with dip-coating stent. Methods We prepared cationic NP encapsulated with a fluorescence marker (FITC) by emulsion solvent diffusion method, succeeded to formulate an NP-eluting stent with a novel cation electrodeposition coating technology, and compared the in vitro and in vivo characteristics of the FITC-loaded NP-eluting stent with dip-coated FITC-eluting stent and bare metal stent. Results The NP was taken up stably and efficiently by cultured vascular smooth muscle cells in vitro. In a porcine coronary artery model in vivo, substantial FITC fluorescence was observed in neointimal and medial layers of the stented segments that had received the FITC-NP-eluting stent until 4 weeks. In contrast, no substantial FITC fluorescence was observed in the segments from the polymer-based FITC-eluting stent or from bare metal stent. The magnitudes of stent-induced injury, inflammation, endothelial recovery, and neointima formation were comparable between bare metal stent and NP-eluting stent groups. Conclusions Therefore, this NP-eluting stent is an efficient NP-mediated DDS that holds as an innovative platform for the delivery of less invasive nano-devices targeting cardiovascular disease. (J Am Coll Cardiol Intv 2009;2:277-83) (C) 2009 by the American College of Cardiology Foundation. |
| 71. | Jun-ichiro Koga, Tetsuya Matoba, Kensuke Egashira, Mitsuki Kubo, Miho Miyagawa, Eiko Iwata, Katsuo Sueishi, Masabumi Shibuya, Kenji Sunagawa, Soluble Flt-1 Gene Transfer Ameliorates Neointima Formation After Wire Injury in flt-1 Tyrosine Kinase-Deficient Mice, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 10.1161/ATVBAHA.109.183772, Vol.29, No.4, pp.458-U48, 2009.04, Objective-We have demonstrated that vascular endothelial growth factor (VEGF) expression is upregulated in injured vascular wall, and blockade of VEGF inhibited monocyte infiltration and neointima formation in several animal models. In the present study, we aimed to clarify relative role of two VEGF receptors, flt-1 versus flk-1/KDR, in neointima formation after injury using flt-1 tyrosine kinase-deficient (Flt-1 TK(-/-)) mice and soluble Flt-1(sFlt-1) gene transfer. Methods and Results-Neointima formation was comparable between wild-type and Flt-1 TK(-/-) mice 28 days after intraluminal wire injury in femoral arteries. By contrast, neointima formation was significantly suppressed by sFlt-1 gene transfer into Flt-1 TK(-/-) mice that blocks VEGF action on flk-1 (intima/media ratio: 2.8 +/- 0.4 versus 1.4 +/- 0.4, P Conclusions-These results suggest that endogenous VEGF accelerates neointima formation through flk-1 by regulating MCP-1 expression in VSMCs and macrophage-mediated inflammation in injured vascular wall in murine model of wire injury. (Arterioscler Thromb Vasc Biol. 2009; 29: 458-464.). |
| 72. | Sato Kei, Egashira Kensuke, Katsuki Shunsuke, Matoba Tetsuya, Sunagawa Kenji, OE-059 Cholesterol-lowering Therapy with the Cholesterol Absorption Inhibitor Ezetimibe Inhibits Plaque Destabilization and Rupture in the Brachiocephalic Arteries of ApoE-deficient Mice(OE10,Atherosclerosis, Basic 1 (IHD),Oral Presentation (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.73, p.189, 2009.03. |
| 73. | Matoba Tetsuya, Egashira Kensuke, Masuda Seigo, Iwata Eiko, Miyagawa Miho, Nakano Kaku, Tukie Noriaki, Sunagawa Kenji, OE-293 Mechanisms Underlying Coronary Vasopsasm at Distal Arterial Segments of Sirolimus-Eluting Stent Implantation in a Porcine Model(OE50,Coronary Circulation/Chronic Coronary Disease (Basic/Clinical) (IHD),Oral Presentation (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.73, pp.248-249, 2009.03. |
| 74. | Satoh Kimio, Nigro Patrizia, Matoba Tetsuya, Shimokawa Hiroaki, Berk Bradford C., OE-298 Cyclophilin A Promotes Vascular Oxidative Stress and Accelerates Development of Angiotensin II-induced Aortic Aneurysms(OE51,Peripheral Circulation/Vascular Disease (Pathophysiology, Basic) (H),Oral Presentation (English),The 73rd Annual Scientific Meeting of The Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.73, p.250, 2009.03. |
| 75. | Kubo Mitsuki, Egashira Kensuke, Oda Shinichiro, Matoba Tetsuya, Hara Kaori, Tsujimoto Hiroyuki, Sunagawa Kenji, OJ-212 Nanoparticle-Mediated Intracellular Delivery of Pitavastatin to Endothelial Progenitor Cells Ex Vivo Recovers the Functional Activity for Therapeutic Neovascularization(OJ36,Peripheral Circulation/Vascular Disease (Therapy) 2 (H),Oral Presentation (Japanese),The 73rd Annual Scientific Meeting of The Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.73, pp.339-340, 2009.03. |
| 76. | Tukie Noriaki, Egashira Kensuke, Kaku Nakano, Matoba Tetsuya, Sunagawa Kenji, PJ-336 Pitavastatin Incorporated Nanoparticle-Eluting Stent Attenuates In-Stent Stenosis, and Prevents Adverse Effects of Silorimus-Eluting Cypher Stent in Porcine Coronary Artery Model(PJ057,Translational Science (Cardiac) (H),Poster Session (Japanese),The 73rd Annual Scientific Meeting of The Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.73, pp.630-631, 2009.03. |
| 77. | Angiotensin 2-induced inflammation and endothelial dysfunction. |
| 78. | Kimio Satoh, Patrizia Nigro, Tetsuya Matoba, Michael R. O'Dell, Zhaoqiang Cui, Xi Shi, Amy Mohan, Chen Yan, Jun-ichi Abe, Bradford C. Berk, Cyclophilin a Promotes Vascular Oxidative Stress and Accelerates Development of Angiotensin II-Induced Aortic Aneurysms, CIRCULATION, Vol.118, No.18, pp.S323-S324, 2008.10. |
| 79. | Tetsuya Matoba, Kensuke Egashira, Seigo Masuda, Eiko Iwata, Miho Miyagawa, Kaku Nakano, Noriaki Tsukie, Kenji Sunagawa, Mechanisms Underlying Coronary Vasopsasm at Distal Arterial Segments of Sirolimus-Eluting Stent Implantation In a Porcine Model, CIRCULATION, Vol.118, No.18, pp.S569-S570, 2008.10. |
| 80. | Jun-ichiro Koga, Kensuke Egashira, Tetsuya Matoba, Kaori Hara, Hiroyuki Tsujimoto, Kenji Sunagawa, Nanoparticle-Mediated Monocyte-Selective Transfection of Dominant-Negative Monocyte Chemoattractant Protein-1 (MCP-1) Gene Inhibits Plaque Rupture in ApoE-Deficient Mice, CIRCULATION, Vol.118, No.18, pp.S510-S511, 2008.10. |
| 81. | Tetsuya Matoba, Kensuko Egashira, Jun-ichiro Koga, Kaori Hara, Hiroyuki Tsujimoto, Kenji Sunagawa, Nanoparticle-based Monocyte-Selective Delivery of PPAR gamma Agonist Pioglitazone Inhibits Plaque Rupture In ApoE-Deficient Mice, CIRCULATION, Vol.118, No.18, pp.S449-S450, 2008.10. |
| 82. | Kimio Satoh, Tetsuya Matoba, Jun Suzuki, Michael R O'Dell, Patrizia Nigro, Zhaoqiang Cui, Amy Mohan, Shi Pan, Lingli Li, Zheng-Gen Jin, Chen Yan, Jun-ichi Abe, Bradford C Berk, Cyclophilin A mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation., Circulation, 10.1161/CIRCULATIONAHA.107.756106, Vol.117, No.24, pp.3088-98, 2008.06, BACKGROUND: Oxidative stress, generated by excessive reactive oxygen species, promotes cardiovascular disease. Cyclophilin A (CyPA) is a 20-kDa chaperone protein secreted from vascular smooth muscle cells (VSMCs) in response to reactive oxygen species that stimulates VSMC proliferation and inflammatory cell migration in vitro; however, the role CyPA plays in vascular function in vivo remains unknown. METHODS AND RESULTS: We tested the hypothesis that CyPA contributes to vascular remodeling by analyzing the response to complete carotid ligation in CyPA knockout mice, wild-type mice, and mice that overexpress CyPA in VSMC (VSMC-Tg). After carotid ligation, CyPA expression in vessels of wild-type mice increased dramatically and was significantly greater in VSMC-Tg mice. Reactive oxygen species-induced secretion of CyPA from mouse VSMCs correlated significantly with intracellular CyPA expression. Intimal and medial hyperplasia correlated significantly with CyPA expression after 2 weeks of carotid ligation, with marked decreases in CyPA knockout mice and increases in VSMC-Tg mice. Inflammatory cell migration into the intima was significantly reduced in CyPA knockout mice and increased in VSMC-Tg mice. Additionally, VSMC proliferation assessed by Ki67(+) cells was significantly less in CyPA knockout mice and was increased in VSMC-Tg mice. The importance of CyPA for intimal and medial thickening was shown by strong correlations between CyPA expression and the number of both inflammatory cells and proliferating VSMCs in vivo and in vitro. CONCLUSIONS: In response to low flow, CyPA plays a crucial role in VSMC migration and proliferation, as well as inflammatory cell accumulation, thereby regulating flow-mediated vascular remodeling and intima formation.. |
| 83. | Koga Junichiro, Matoba Tetsuya, Egashira Kensuke, Hara Kaori, Tsujimoto Hiroyuki, Sueishi Katsuo, Sunagawa Kenji, FRS-029 Monocyte-Targeting Nanoparticle-Based Delivery of Anti-Monocyte Chemoattractant Protein-1 Gene Inhibits Plaque Rupture of Brachiocephalic Arteries in Apolipoprotein-E Deficient Mice(Novel Mechanisms in Atherosclerosis (IHD),Featured Research Session,The 72nd Annual Scientific Meeting of the Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.72, p.149, 2008.03. |
| 84. | Koga Jun-ichiro, Matoba Tetsuya, Egashira Kensuke, Hara Kaori, Tsujimoto Hiroyuki, Sueishi Katsuo, Sunagawa Kenji, OE-188 Monocyte-targeting Nanoparticle-based Delivery of Pioglitazone Inhibits Plaque Rupture in the Brachiocephalic Arteries of Apolipoprotein-E Deficient Mice(Atherosclerosis, basic(01)(IHD),Oral Presentation(English),The 72nd Annual Scientific Meeting of the Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.72, p.227, 2008.03. |
| 85. | Chemokines in atherosclerosis. |
| 86. | Kimio Satoh, Tetsuya Matoba, Michael O'Dell, Lingli Li, Jun Suzuki, Shi Pan, Sarah Mack, Amy Mohan, Zheng-Gen Jin, Joseph M. Milano, Jun-ichi Abe, Bradford C. Berk, Cyclophilin a mediates vascular remodeling by promoting inflammation and vascular smooth muscle cell proliferation, CIRCULATION, Vol.116, No.16, pp.149-150, 2007.10. |
| 87. | Jun-ichiro Koga, Kensuke Egashira, Tetsuya Matoba, Masabumi Shibuya, Kenji Sunagawa, VEGF accelerates neointima formation through flk-1 after wire injury in flt-1 tyrosine kinase-deficient mice, HYPERTENSION, Vol.50, No.4, p.E106, 2007.10. |
| 88. | Jun-ichiro Koga, Kensuke Egashira, Tetsuya Matoba, Masabumi Shibuya, Kenji Sunagawa, Vascular endothelial growth factor accelerates neointima formation through flk-1 after wire injury in flt-1 tyrosine kinase-deficient mice, CIRCULATION, Vol.116, No.16, pp.237-238, 2007.10. |
| 89. | Jun Suzuki, Zheng-Gen Jin, David F Meoli, Tetsuya Matoba, Bradford C Berk, Cyclophilin A is secreted by a vesicular pathway in vascular smooth muscle cells., Circulation research, 10.1161/01.RES.0000216405.85080.a6, Vol.98, No.6, pp.811-7, 2006.03, Reactive oxygen species (ROS) contribute to the pathogenesis of atherosclerosis in part by promoting vascular smooth muscle cell (VSMC) growth. Previously we demonstrated that cyclophilin A (CyPA) is a secreted oxidative stress-induced factor (SOXF) that promotes inflammation, VSMC growth, and endothelial cell apoptosis. However, the mechanisms that regulate CyPA secretion are unknown. In this study, we hypothesized that ROS-induced CyPA secretion from VSMC requires a highly regulated process of vesicle transport, docking, and fusion at the plasma membrane. Conditioned medium and plasma membrane sheets were prepared by exposing VSMC to 1 micromol/L LY83583, which generates intracellular superoxide. A vesicular transport mechanism was confirmed by colocalization at the plasma membrane with vesicle-associated membrane protein (VAMP). CyPA transport to the plasma membrane and secretion were significantly increased by LY83583. Reduction of VAMP-2 expression by small interfering RNA inhibited LY83583-induced CyPA secretion. Pretreatment with 3 micromol/L cytochalasin D, an actin depolymerizing agent, abrogated CyPA secretion. Infection with dominant-negative RhoA and Cdc42 adenovirus inhibited CyPA secretion by 72% and 63%, respectively, whereas dominant-negative Rac1 had a small effect (11%). Pretreatment with the Rho kinase inhibitor Y27632 (3 to 30 micromol/L) and myosin II inhibitor blebbistatin (1 to 10 micromol/L) inhibited CyPA secretion in a dose-dependent manner. Simvastatin (3 to 30 micromol/L) also dose-dependently inhibited LY83583-induced CyPA secretion likely via decreased isoprenylation of small GTPases. Our findings define a novel VSMC vesicular secretory pathway for CyPA that involves actin remodeling and myosin II activation via RhoA-, Cdc42-, and Rho kinase-dependent signaling events.. |
| 90. | Yoshihiro Fukumoto, Akira Ito, Toyokazu Uwatoku, Tetsuya Matoba, Takuya Kishi, Haruki Tanaka, Akira Takeshita, Kenji Sunagawa, Hiroaki Shimokawa, Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease., Coronary artery disease, 10.1097/00019501-200602000-00011, Vol.17, No.1, pp.63-70, 2006.02, OBJECTIVE: Prognosis of severe coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting remains poor. We have recently demonstrated that shock wave therapy effectively induces neovascularization and improves myocardial ischemia in a porcine model in vivo. METHODS: With permission from the Ethical Committee of our Institute, we treated nine patients with end-stage coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting (55-82 years old, five men and four women) with our cardiac shock wave therapy (200 shots/spot at 0.09 mJ/mm for 20-40 spots, 3 times a week/series). We followed-up the patients at 1, 3, 6, and 12 months after the therapy to examine the amelioration of myocardial ischemia. When needed, shock wave therapy was performed up to three series at 0, and 1, 3 or 6 months. RESULTS: The cardiac shock wave therapy improved symptoms (Canadian Cardiovascular Society functional class score, from 2.7+/-0.2 to 1.8+/-0.2, P |
| 91. | Extracorporeal Cardiac Shock Wave Therapy Ameliorates Myocardial Ischemia in Patients With Severe Coronary Artery Disease. |
| 92. | J Suzuki, T Matoba, ZG Jin, BC Berk, HMG-CoA reductase inhibitor attenuates reactive oxygen species-induced cyclophilin a secretion in vascular smooth muscle cells: Role for actin and Rho GTPases, CIRCULATION, Vol.112, No.17, p.U270, 2005.10. |
| 93. | Keiko Morikawa, Tetsuya Matoba, Hiroshi Kubota, Makoto Hatanaka, Takako Fujiki, Shosuke Takahashi, Akira Takeshita, Hiroaki Shimokawa, Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated responses in mice., Journal of cardiovascular pharmacology, 10.1097/01.fjc.0000159657.93922.cb, Vol.45, No.5, pp.485-90, 2005.05, The endothelium synthesizes and releases several vasodilator substances, including vasodilator prostaglandins, NO, and EDHF. NO-mediated relaxations are reduced by various risk factors, such as diabetes mellitus and hypercholesterolemia. However, it remains to be elucidated whether EDHF-mediated relaxations also are reduced by those factors and their combination. In this study, we addressed this point in mice. We used small mesenteric arteries from control, diabetic (streptozotocin-induced), apolipoprotein-E-deficient (ApoE-/-), and diabetic ApoE-/- mice. In control mice, endothelium-dependent relaxations to acetylcholine were largely mediated by EDHF. This EDHF-mediated component was slightly reduced in diabetic mice, preserved in ApoE-/- mice, and markedly reduced in diabetic ApoE-/- mice with an increase in NO-mediated component and a negative contribution of indomethacin-sensitive endothelium-derived contracting factor (EDCF). Endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of calcium-activated K channels, were attenuated in ApoE-/- and diabetic ApoE-/- mice. Endothelium-dependent hyperpolarizations were significantly reduced in diabetic mice, preserved in ApoE-/- mice, and again markedly reduced in diabetic ApoE-/- mice. These results indicate that hypercholesterolemia alone minimally affects the EDHF-mediated relaxations, and diabetes mellitus significantly attenuated the responses, whereas their combination markedly attenuates the responses with a compensatory involvement of NO and a negative contribution of EDCF.. |
| 94. | Takako Fujiki, Hiroaki Shimokawa, Keiko Morikawa, Hiroshi Kubota, Makoto Hatanaka, M A Hassan Talukder, Tetsuya Matoba, Akira Takeshita, Kenji Sunagawa, Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin-converting enzyme inhibitor on endothelium-derived hyperpolarizing factor-mediated responses in mice., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/01.ATV.0000158498.19027.75, Vol.25, No.4, pp.766-71, 2005.04, UNLABELLED: Background- We have recently identified that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans, for which endothelial nitric oxide synthase (eNOS) is an important source. Angiotensin-converting enzyme (ACE) inhibitors are known to enhance EDHF-mediated responses. In this study, we examined whether endothelium-derived H2O2 accounts for the enhancing effect of an ACE inhibitor on EDHF-mediated responses and, if so, what mechanism is involved. METHODS AND RESULTS: Control and eNOS-/- mice were maintained with or without temocapril (10 mg/kg per day orally) for 4 weeks, and isometric tensions and membrane potentials of mesenteric arteries were recorded. In control mice, temocapril treatment significantly enhanced EDHF-mediated relaxations and hyperpolarizations to acetylcholine (n=8 each). Catalase, a specific scavenger of H2O2, abolished the beneficial effects of temocapril, although it did not affect endothelium-independent relaxations to sodium nitroprusside or NS1619, a direct opener of K(Ca) channels (n=6 each). Western blot analysis demonstrated that the temocapril treatment significantly upregulated the expression of eNOS. By contrast, this enhancing effect of temocapril was absent in eNOS-/- mice (n=6). CONCLUSIONS: These results indicate that endothelium-derived H2O2 accounts for the enhancing effect of temocapril on EDHF-mediated responses caused in part by eNOS upregulation, further supporting our H2O2 theory.. |
| 95. | Y Fukumoto, T Matoba, A Ito, H Tanaka, T Kishi, S Hayashidani, K Abe, A Takeshita, H Shimokawa, Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension, HEART, 10.1136/hrt.2003.029470, Vol.91, No.3, pp.391-392, 2005.03. |
| 96. | Fujiki Takako, Shimokawa Hiroaki, Morikawa Keiko, Kubota Hiroshi, Hatanaka Makoto, Hassan Talukder M. A., Matoba Tetsuya, Takeshita Akira, Sunagawa Kenji, Endothelium-Derived Hydrogen Peroxide Accounts for the Enhancing Effect of an ACE Inhibitor on EDHF-Mediated Responses in Mice(Endothelium/NO 2 (H), The 69th Annual Scientific Meeting of the Japanese Circulation Society), Circulation journal : official journal of the Japanese Circulation Society, Vol.69, p.394, 2005.03. |
| 97. | Keiko Morikawa, Takako Fujiki, Tetsuya Matoba, Hiroshi Kubota, Makoto Hatanaka, Shosuke Takahashi, Hiroaki Shimokawa, Important role of superoxide dismutase in EDHF-mediated responses of human mesenteric arteries., Journal of cardiovascular pharmacology, 10.1097/00005344-200411000-00006, Vol.44, No.5, pp.552-6, 2004.11, The endothelium synthesizes and releases several vasodilator substances, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have identified hydrogen peroxide (H2O2) as an EDHF in mouse and human mesenteric arteries and porcine coronary microvessels. We also have recently demonstrated that Cu,Zn-SOD plays an important role in EDHF synthesis in mouse mesenteric arteries. However, it remains to be determined whether SOD also plays an important role in EDHF-mediated responses of human arteries. In this study, we addressed this point in human mesenteric arteries. We used small mesenteric arteries of patients who underwent gastrectomy operations. Isometric tensions and membrane potentials were recorded in the presence of indomethacin and N-nitro-L-arginine to inhibit the synthesis of prostacyclin and NO, respectively. Pretreatment with Tiron, a cell-permeable SOD-mimetic, significantly enhanced the EDHF-mediated relaxations and hyperpolarizations to bradykinin, and this effect was abolished by catalase, indicating that this enhancing effect was achieved by H2O2. By contrast, Tiron did not affect endothelium-independent relaxations, indicating that the enhancing effect of Tiron is not caused by the enhancement of vascular smooth muscle responses. These results indicate that SOD plays an important role in EDHF-mediated relaxations and hyperpolarizations of human mesenteric arteries.. |
| 98. | T Fujiki, M Hatanaka, K Morikawa, H Kubota, T Matoba, MAH Talukder, H Shimokawa, Endothelium-derived hydrogen peroxide accounts for the enhanced EDHF-mediated relaxation by long-term treatment with an angiotensin-converting enzyme inhibitor in mice, CIRCULATION, Vol.110, No.17, p.77, 2004.10. |
| 99. | K Morikawa, H Kubota, T Matoba, T Fujiki, M Hatanaka, H Shimokawa, Important role of superoxide dismutase in EDHF-mediated relaxations of human mesenteric arteries, CIRCULATION, Vol.110, No.17, p.54, 2004.10. |
| 100. | K Morikawa, H Kubota, T Matoba, T Fujiki, M Hatanaka, Influence of diabetes mellitus, hypercholesterolemia, and their combination on EDHF-mediated relaxations in mice, CIRCULATION, Vol.110, No.17, pp.76-77, 2004.10. |
| 101. | K Inokuchi, A Ito, Y Fukumoto, T Matoba, A Shiose, T Nishida, M Masuda, S Morita, H Shimokawa, Usefulness of fasudil, a rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery, JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 10.1097/01.fjc.0000134775.76636.3f, Vol.44, No.3, pp.275-277, 2004.09, We have recently demonstrated that fasudil, a Rho-kinase inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the inhibitory effect of fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosoroide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.. |
| 102. | K Morikawa, H Kubota, T Matoba, M Hatanaka, T Fujiki, MAH Talukder, T Akaike, H Maeda, H Shimokawa, Endothelial Cu,Zn-SOD plays a pivotal role in endothelium-dependent hyperpolarization in mice, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 10.1016/j.niox.2004.07.003, Vol.11, No.1, p.48, 2004.08. |
| 103. | T Fujiki, H Kubota, M Hatanaka, K Morikawa, MAH Talukder, T Matoba, H Shimokawa, Endothelium-derived hydrogen peroxide accounts for the enhanced EDHF-mediated relaxations by long-term treatment with an angiotensin converting enzyme inhibitor in mice, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, Vol.11, No.1, p.73, 2004.08. |
| 104. | K Morikawa, H Kubota, T Matoba, M Hatanaka, T Fujiki, MAH Talukder, H Shimokawa, Important role of superoxide dismutase in EDHF-mediated relaxations of human mesenteric arteries, NITRIC OXIDE-BIOLOGY AND CHEMISTRY, Vol.11, No.1, p.57, 2004.08. |
| 105. | H Shimokawa, T Matoba, Hydrogen peroxide as an endothelium-derived hyperpolarizing factor, PHARMACOLOGICAL RESEARCH, 10.1016/j.phrs.2003.10.016, Vol.49, No.6, pp.543-549, 2004.06, Vascular endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, such as prostacyclin, nitric oxide (NO), Mid a Yet unidentified endothelium-derived hyperpolarizing, Factor (EDHF). Possible candidates for EDHF include epoxyeicosatrienoic acids (EETs), endothelium-derived potassium ions (K+), and as we have recently identified, hydrogen peroxide (H2O2). Electrical communication between endothelial and smooth muscle cells through gap junctions has also been suggested to be involved in endothelium-dependent hyperpolarization. Among the above candidates, the H2O2 hypothesis well explains the pathophysiological interactions between NO and EDHF and re-highlights the physiological roles of the reactive Oxygen Species (ROS) in endothelium-dependent vascular responses. This brief review summarizes our current knowledge about H2O2 as an EDHF, with special reference to its production by the endothelium, its action on membrane potentials and its pathophysiological roles. (C) 2004 Elsevier Ltd. All rights reserved.. |
| 106. | Fujiki Takako, Kubota Hiroshi, Morikawa Keiko, Hatanaka makkoto, Matoba Tetsuya, Hassan Talukder M. A., Shimokawa Hiroaki, OE-303 Hydorogen Peroxide Is an Endothelium-Derived Hyperpolaring Factor (EDHF) Involved in the Beneficial Effect of an ACE Inhibitorin Mice(Endothelium/NO 4 (H) : OE38)(Oral Presentation (English)), Circulation journal : official journal of the Japanese Circulation Society, Vol.68, p.214, 2004.03. |
| 107. | Morikawa Keiko, Kubota Hiroshi, Matoba Tetsuya, Hatanaka Makoto, Fujiki Takako, Hassan Talukder M. A., Shimokawa Hiroaki, OE-305 Important Role of Superoxide Dismutase in EDHF-Mediated Relaxations of Human Mesenteric Arteries(Endothelium/NO 4 (H) : OE38)(Oral Presentation (English)), Circulation journal : official journal of the Japanese Circulation Society, Vol.68, p.214, 2004.03. |
| 108. | Inokuchi Kosuke, Ito Akira, Fukumoto Yoshihiro, Matoba Tetsuya, Shiose Akira, Nishida Takahiro, Masuda Munetaka, Morita Shigeki, Shimokawa Hiroaki, PJ-180 Usefulness of Fasudil, a Rho-Kinase Inhibitor, to Treat Intractable Severe Vasopasm After Coronary Artery Bypass Surgery(Cardiovascular Surgery/CABG 2 (IHD) : PJ31)(Poster Session (Japanese)), Circulation journal : official journal of the Japanese Circulation Society, Vol.68, p.524, 2004.03. |
| 109. | K Morikawa, H Shimokawa, T Matoba, H Kubota, T Akaike, MAH Talukder, M Hatanaka, T Fujiki, H Maeda, S Takahashi, A Takeshita, Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization, JOURNAL OF CLINICAL INVESTIGATION, 10.1172/JCI200319351, Vol.112, No.12, pp.1871-1879, 2003.12, The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, NO, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived H2O2 is an EDHF in mesenteric arteries of mice and humans and in porcine coronary microvessels. However, the mechanism for the endothelial production of H2O2 as an EDHF remains to be elucidated. In this study, we tested our hypothesis that Cu,Zn-superoxide dismutase (Cu,Zn-SOD) plays a pivotal role in endothelium-dependent hyperpolarization, using control and CuZn-SOD-/- mice. In mesenteric arteries, EDHF-mediated relaxations and hyperpolarizations were significantly reduced in Cu,Zn-SOD-/- mice with no inhibitory effect of catalase, while endothelium-independent relaxations and hyperpolarizations were preserved. Endothelial H2O2 production also was significantly reduced in CuZn-SOD-/- mice. In Langendorff isolated heart, bradykinin-induced increase in coronary flow was significantly reduced in CuZn-SOD-/- mice, again with no inhibitory effect of catalase. The exogenous SOD mimetic tempol significantly improved EDHF-mediated relaxations and hyperpolarizations and coronary flow response in CuZn-SOD-/- mice. These results prove the novel concept that endothelial Cu,Zn-SOD plays an important role as an "EDHF synthase" in mice, in addition to its classical role to scavenge superoxide anions.. |
| 110. | Advanced Cardiovascular Life Support (ACLS). |
| 111. | T Fujiki, H Kubota, K Morikawa, T Matoba, MAH Talukder, M Hatanaka, H Shimokawa, Endothelium-derived hydrogen peroxide accounts for the improved EDHF-mediated relaxations caused by long-term treatment with an angiotensin converting enzyme inhibitor in mice, CIRCULATION, Vol.108, No.17, p.192, 2003.10. |
| 112. | Y Fukumoto, T Matoba, K Abe, A Ito, H Shimokawa, Rho-kinase inhibitor, fasudil, reduces pulmonary vascular resistance in patients with severe pulmonary hypertension, CIRCULATION, Vol.108, No.17, p.525, 2003.10. |
| 113. | Yasushi Mukai, Hiroaki Shimokawa, Tetsuya Matoba, Junko Hiroki, Ikuko Kunihiro, Takako Fujiki, Akira Takeshita, Acute vasodilator effects of HMG-CoA reductase inhibitors: involvement of PI3-kinase/Akt pathway and Kv channels., Journal of cardiovascular pharmacology, 10.1097/00005344-200307000-00018, Vol.42, No.1, pp.118-24, 2003.07, 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase inhibitors (statins) have several non-lipid-lowering actions; however, characteristics of their acute vasodilator effects remain to be elucidated. In this study, acute vasodilator effects of statins were examined in isolated rat blood vessels. After incubation with cerivastatin (1 microM) for 2 hours, acetylcholine-induced endothelium-dependent relaxations were enhanced in the rat aorta. This effect was abolished by a nitric oxide synthase (NOS) inhibitor, L-NNA, and by a PI3 kinase inhibitor, LY294002. Western blot analysis showed that the extent of phosphorylation of Akt, an active form of Akt, was increased by cerivastatin while it was reduced by LY294002, suggesting an involvement of PI3 kinase/Akt-dependent activation of endothelial NOS. At higher concentrations (1-300 microM), both cerivastatin and fluvastatin, but not pravastatin, directly relaxed the blood vessels, regardless of the presence or absence of the endothelium. These relaxations were abolished by KCl and were significantly inhibited by an inhibitor of Kv channel, 4-aminopyridine. These results indicate that multiple mechanisms are involved in the acute vasodilator effects of statins, including augmentation of nitric oxide-mediated endothelium-dependent relaxations through the PI3 kinase/Akt pathway and endothelium-independent relaxations via Kv channel-mediated smooth muscle hyperpolarizations. These acute vasodilator effects of statins may account, at least in part, for their beneficial effects on cardiovascular diseases associated with impaired organ blood flow.. |
| 114. | T Matoba, H Shimokawa, K Morikawa, H Kubota, Kunihiro, I, L Urakami-Harasawa, Y Mukai, Y Hirakawa, T Akaike, A Takeshita, Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 10.1161/01.ATV.0000078601.79536.6C, Vol.23, No.7, pp.1224-1230, 2003.07, Objective-Endothelium-derived hyperpolarizing factor ( EDHF) plays an important role in modulating vascular tone, especially in microvessels, although its nature has yet to be elucidated. This study was designed to examine whether hydrogen peroxide (H2O2) is an EDHF in porcine coronary microvessels with use of an electron spin resonance (ESR) method to directly detect H2O2 production from the endothelium. Methods and Results-Isometric tension and membrane-potential recordings demonstrated that bradykinin and substance P caused EDHF-mediated relaxations and hyperpolarizations of porcine coronary microvessels in the presence of indomethacin and N-omega-nitro-L-arginine. The contribution of H2O2 to the EDHF-mediated responses was demonstrated by the inhibitory effect of catalase and by the relaxing and hyperpolarizing effects of exogenous H2O2. Endothelial production of H2O2 was quantified in bradykinin- or substance P-stimulated intact blood vessels by ESR spectroscopy. Tiron, a superoxide scavenger that facilitates H2O2 formation, enhanced bradykinin- induced production of H2O2, as well as the EDHF-mediated relaxations and hyperpolarizations. By contrast, cytochrome P-450 inhibitors ( sulfaphenazole or 17-octadecynoic acid) or a gap junction inhibitor (18alpha-glycyrrhetinic acid) failed to inhibit the EDHF-mediated relaxations. Involvement of endothelium-derived K+ was not evident in experiments with ouabain plus Ba2+ or exogenous K+. Conclusion-These results provide ESR evidence that H2O2 is an EDHF in porcine coronary microvessels.. |
| 115. | T Matoba, H Shimokawa, Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans, JOURNAL OF PHARMACOLOGICAL SCIENCES, 10.1254/jphs.92.1, Vol.92, No.1, pp.1-6, 2003.05, Vascular endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, such as prostacyclin, nitric oxide (NO), and a yet unidentified endothelium-derived hyperpolarizing factor (EDHF). Possible candidates for EDHF include epoxyeicosatrienoic acids, endothelium-derived K+ ions, and as we have recently identified, hydrogen peroxide (H2O2). Electrical communication between endothelial and smooth muscle cells through gap junctions has also been suggested to be involved in endothelium-dependent hyperpolarization. Among the above candidates, the H2O2 hypothesis well explains the pathophysiological interactions between NO and EDHF and re-highlights the physiological roles of the reactive oxygen species in endothelium-dependent vascular responses. This brief review summarizes our current knowledge about H2O2 as an EDHF, with special reference to its production by the endothelium, its action on membrane potentials and its pathophysiological roles.. |
| 116. | 血管トーヌス制御 (血管医学 4). |
| 117. | MAH Talukder, H Shimokawa, T Fujiki, K Morikawa, H Kubota, T Matoba, A Takeshita, Involvement of neuronal NO synthase in NO-cGMP-mediated pathway in the maintenance of bradykinin-induced coronary flow in endothelial NO synthase knockout mice, FASEB JOURNAL, Vol.17, No.4, p.A504, 2003.03. |
| 118. | Talukder M.A. Hassan, Shimokawa Hiroaki, Fujiki Takako, Morikawa Keiko, Kubota Hiroshi, Matoba Tetsuya, Takeshita Akira, Compensatory Role of Neuronal NO Synthase in Maintaining Coronary Flow in the Absence of Endothelial NO Synthase in Mice, Circulation journal : official journal of the Japanese Circulation Society, Vol.67, p.264, 2003.03. |
| 119. | Matoba Tetsuya, Shimokawa Hiroaki, Takeshita Akira, Identification of Hydrogen Peroxide as an Endothelium-Derived Hyperpolarizing Factor in Animals and Humans, Circulation journal : official journal of the Japanese Circulation Society, Vol.67, p.88, 2003.03. |
| 120. | Talukder M.A. Hassan, Shimokawa Hiroaki, Morikawa Keiko, Fujiki Takako, Kubota Hiroshi, Kunihiro Ikuko, Matoba Tetsuya, Takeshita Akira, Involvement of Endothelial NO Synthase-Independent Mechanismin the Beneficial Effects of ACE Inhibitor on Coronary Endothelial Functions in Mice, Circulation journal : official journal of the Japanese Circulation Society, Vol.67, p.264, 2003.03. |
| 121. | K Morikawa, T Matoba, H Kubota, T Fujiki, MAH Talukder, Y Hirakawa, H Shimokawa, Important role of Cu/Zn-SOD in the synthesis of endothelium-derived hyperpolarizing factor (EDHF) in mice, CIRCULATION, Vol.106, No.19, p.317, 2002.11. |
| 122. | Y Mukai, H Shimokawa, M Higashi, K Morikawa, T Matoba, J Hiroki, Kunihiro, I, HMA Talukder, A Takeshita, Inhibition of renin-angiotensin system ameliorates endothelial dysfunction associated with aging in rats, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 10.1161/01.ATV.0000029121.63691.CE, Vol.22, No.9, pp.1445-1450, 2002.09, Objective-Endothelial vasodilator functions are progressively impaired with aging, which may account in part for the increased incidence of cardiovascular events in elderly people. We examined what treatment could ameliorate the endothelial dysfunction associated with aging in rats. Methods and Results-Aged (12-month-old) Wistar-Kyoto rats were treated with vehicle, temocapril, CS-866 (an angiotensin II type I receptor antagonist), cerivastatin, or hydralazine for 2 weeks. Endothelium-dependent relaxations (EDRs) of aortas from aged rats were markedly impaired compared with EDRs of aortas from young (3-month-old) rats. Indomethacin, NS-398 (a cyclooxygenase [COX]-2 inhibitor), and SQ-29548 (a thromboxane A(2)/prostaglandin H-2 receptor antagonist) acutely restored EDRs in aged rats, suggesting an involvement of COX-2-derived vasoconstricting eicosanoids. Tiron, a superoxide scavenger, also partially improved EDRs, suggesting an involvement of superoxide. EDRs were significantly ameliorated in aged rats after long-term treatment with temocapril or CS-866 but not after treatment with cerivastatin or hydralazine. Indomethacin induced no further improvement of EDRs after treatment with temocapril or CS-866. COX-2 protein expression and superoxide production were increased in the aortas of aged rats and were also attenuated by treatment with temocapril or CS-866. Conclusions-These results demonstrate that long-term inhibition of the renin-angiotensin system ameliorates endothelial dysfunction associated with aging through the inhibition of the synthesis of COX-2-derived vasoconstricting factors and superoxide anions.. |
| 123. | H2O2による血管調節機能 —内皮由来過分極因子としてのH2O2- (医学のあゆみ 8). |
| 124. | 内皮由来過分極因子としての過酸化水素 (血管医学 3). |
| 125. | Matoba Tetsuya, Shimokawa Hiroaki, Kubota Hiroshi, Kunihiro Ikuko, Morikawa Keiko, Fujiki Takako, Takeshita Akira, Evidence for heterogeneity of the nature of endothelium-derived hyperpolarizing factors (EDHF) in porcine coronary arteries, Circulation journal : official journal of the Japanese Circulation Society, Vol.66, p.115, 2002.03. |
| 126. | Matoba Tetsuya, Shimokawa Hiroaki, Kubota Hiroshi, Morikawa Keiko, Fujiki Takako, Takeshita Akira, Hydrogen peroxide is an endothelium-derived hyperpolarizing factor (EDHF) in human mesenteric arteries, Circulation journal : official journal of the Japanese Circulation Society, Vol.66, p.192, 2002.03. |
| 127. | Shimokawa Hiroaki, Matoba Tetsuya, Takeshita Akira, Identification of endothelium-derived hyperpolarizing factor : an evolving concept on endothelium-derived relaxing factors, Circulation journal : official journal of the Japanese Circulation Society, Vol.66, p.13, 2002.03. |
| 128. | Mukai Yasushi, Shimokawa Hiroaki, Matoba Tetsuya, Hiroki Junko, Higashi Midoriko, Kunihiro Ikuko, Takeshita Akira, Inhibition of renin-angiotensin system ameliorates endothelial dysfunction with aging in rats, Circulation journal : official journal of the Japanese Circulation Society, Vol.66, p.377, 2002.03. |
| 129. | Mukai Yasushi, Shimokawa Hiroaki, Matoba Tetsuya, Hiroki Junko, Fujiki Takako, Kunihiro Ikuko, Takeshita Akira, Novel mechanisms for acute vasodilating effects of statins : Multiple actions on the endothelium and vascular smooth muscle cells, Circulation journal : official journal of the Japanese Circulation Society, Vol.66, p.320, 2002.03. |
| 130. | Tadashi Kandabashi, Hiroaki Shimokawa, Yasushi Mukai, Tetsuya Matoba, Ikuko Kunihiro, Keiko Morikawa, Masaaki Ito, Shosuke Takahashi, Kozo Kaibuchi, Akira Takeshita, Involvement of rho-kinase in agonists-induced contractions of arteriosclerotic human arteries., Arteriosclerosis, thrombosis, and vascular biology, 10.1161/hq0202.104274, Vol.22, No.2, pp.243-8, 2002.02, Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart diseases. We have recently demonstrated that Rho-kinase plays a key role in the spasm in our porcine model. However, it remains to be elucidated whether Rho-kinase-mediated pathway also contributes to vasoconstriction of human arteries. From 15 patients who underwent coronary artery bypass operation, segments of isolated left internal thoracic arteries were obtained, and the endothelium was gently removed. Serotonin and histamine caused contractions, which were markedly inhibited by a specific Rho-kinase inhibitor, hydroxyfasudil. Western blot analysis showed that, during the serotonin-induced contractions, the extent of phosphorylation of myosin-binding subunit of myosin phosphatase (MBS, one of the major substrates of Rho-kinase) was significantly increased in the specimens. Hydroxyfasudil again significantly suppressed the serotonin-induced increase in MBS phosphorylation. There was a significant positive correlation between the extent of MBS phosphorylation and that of the serotonin-induced contractions and between hydroxyfasudil-sensitive components of the contractions and the extent of arteriosclerosis. These results indicate that Rho-kinase plays an important role in vascular smooth muscle contractions of arteriosclerotic human arteries, suggesting that Rho-kinase could be regarded as an important target for the treatment of arteriosclerotic vascular diseases in humans.. |
| 131. | Tetsuya Matoba, Hiroaki Shimokawa, Hiroshi Kubota, Keiko Morikawa, Takako Fujiki, Ikuko Kunihiro, Yasushi Mukai, Yoji Hirakawa, Akira Takeshita, Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries., Biochemical and biophysical research communications, 10.1006/bbrc.2001.6278, Vol.290, No.3, pp.909-13, 2002.01, The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived hydrogen peroxide (H(2)O(2)) is an EDHF in mice. The present study was designed to examine whether this is also the case in humans. Bradykinin elicited endothelium-dependent relaxations and hyperpolarizations in the presence of indomethacin and N(omega)-nitro-l-arginine, which thus were attributed to EDHF, in human mesenteric arteries. The EDHF-mediated relaxations were significantly inhibited by catalase, an enzyme that specifically decomposes H(2)O(2), whereas catalase did not affect endothelium-independent hyperpolarizations to levcromakalim. Exogenous H(2)O(2) elicited relaxations and hyperpolarizations in endothelium-stripped arteries. Gap junction inhibitor 18alpha-glycyrrhetinic acid partially inhibited, whereas inhibitors of cytochrome P450 did not affect the EDHF-mediated relaxations. These results indicate that H(2)O(2) is also a primary EDHF in human mesenteric arteries with some contribution of gap junctions.. |
| 132. | Y Mukai, T Matoba, J Hiroki, T Kandabashi, Acute vasodilating effects of statins - A novel concept on their pharmacological actions-, CIRCULATION, Vol.104, No.17, p.213, 2001.10. |
| 133. | T Matoba, H Kubota, Y Mukai, Kunihiro, I, K Morikawa, Y Hirakawa, H Shimokawa, Evidence for heterogeneity of the nature of endothelium-derived hyperpolarizing factors in porcine coronary arteries, CIRCULATION, Vol.104, No.17, p.40, 2001.10. |
| 134. | T Matoba, H Kubota, Kunihiro, I, K Morikawa, Y Mukai, Y Hirakawa, Hydrogen peroxide is an endothelium-derived hyperpolarizing factor (EDHF) in human mesenteric arteries, CIRCULATION, Vol.104, No.17, p.286, 2001.10. |
| 135. | M Higashi, Y Mukai, T Matoba, J Hiroki, Kunihiro, I, H Shimokawa, Long-term inhibition of Rho-kinase suppresses angiotensin II-induced formation of coronary vascular lesions and cardiac hypertrophy in rats in vivo, CIRCULATION, Vol.104, No.17, p.325, 2001.10. |
| 136. | T Kandabashi, Kunihiro, I, Y Mukai, T Matoba, K Morikawa, H Shimokawa, Rho-kinase plays an important role for vascular smooth muscle contraction of atherosclerotic human arteries, CIRCULATION, Vol.104, No.17, p.298, 2001.10. |
| 137. | Shimokawa H, Matoba T, Does EDHF contribute to the control of peripehral resistance? (Dialogues Cardiovasc Med), Dialogues Cardiovasc Med, Vol.6, pp.235-239, 2001.09. |
| 138. | Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension.. |
| 139. | T Matoba, H Shimokawa, M Nakashima, Y Hirakawa, Y Mukai, K Hirano, H Kanaide, A Takeshita, Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice, JOURNAL OF CLINICAL INVESTIGATION, Vol.106, No.12, pp.1521-1530, 2000.12, The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several endothelium-derived relaxing factors, such as prostacyclin, nitric oxide (NO), and the previously unidentified endothelium-derived hyperpolarizing factor (EDHF). In this study, we examined our hypothesis that hydrogen peroxide (H2O2) derived from endothelial NO synthase (eNOS) is an EDHF. EDHF-mediated relaxation and hyperpolarization in response to acetylcholine (ACh) were markedly attenuated in small mesenteric arteries from eNOS knockout (eNOS-KO) mice. In the eNOS-KO mice, vasodilating and hyperpolarizing responses of vascular smooth muscle per se were fairly well preserved, as was the increase in intracellular calcium in endothelial cells in response to ACh, Antihypertensive treatment with hydralazine failed to improve the EDHF-mediated relaxation. Catalase, which dismutates H2O2 to form water and oxygen, inhibited EDHF-mediated relaxation and hyperpolarization, but it did not affect endothelium-independent relaxation following treatment with the K+ channel opener levcromakalim. Exogenous H2O2 elicited similar relaxation and hyperpolarization in endothelium-stripped arteries. Finally, laser confocal microscopic examination with peroxide-sensitive fluorescence dye demonstrated that: the endothelium produced H2O2 upon stimulation by ACh acid that the H2O2 production was markedly reduced in eNOS-KO mice. These results indicate that H2O2 is an EDHF in mouse small mesenteric arteries and that eNOS is a major source of the reactive oxygen species.. |
| 140. | T Matoba, H Shimokawa, M Nakashima, Y Mukai, A Takeshita, Hydrogen peroxide derived from endothelial nitric oxide synthase is an endothelium-derived hyperpolarizing factor (EDHF) in mice, CIRCULATION, Vol.102, No.18, p.303, 2000.10. |
| 141. | T Matoba, H Shimokawa, Kunihiro, I, M Nakashima, Endothelium-derived hyperpolarizing factor (EDHF) is an endothelial nitric oxide synthase (eNOS)-Derived non-NO factor in mice, CIRCULATION, Vol.100, No.18, p.487, 1999.11. |
| 142. | NOとEDHF (循環器科 44). |
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