The possibility of pleiotropic effects of Novel Oral Anticoagulants (NOAC) on Rho-kinase-cyclophilin A System

• Project/Area Number: 25670379
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Tohoku University
• Principal Investigator: SHIMOKAWA Hiroaki 東北大学, 医学(系)研究科(研究院), 教授 (00235681)
• Co-Investigator(Kenkyū-buntansha): SATOH Kimio 東北大学, 高度教養教育・学生支援機構, 准教授 (80436120)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: シグナル伝達 / スタチン / 低分子量G蛋白 / サイクロフィリンA / 心血管疾患 / 平滑筋増殖 / バイオマーカー / Rhoキナーゼ / 新規抗凝固薬 / Xa阻害薬

Outline of Final Research Achievements

We tested our hypothesis that small GTP-binding protein GDP dissociation stimulator (SmgGDS) plays a crucial role in the molecular mechanisms of the Rac1 signaling pathway inhibition by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in endothelial cells. In the present study, we demonstrated that statins exert their pleiotropic effects through SmgGDS upregulation with a resultant Rac1 degradation and reduced oxidative stress in animals and humans.

Research Products

• [Journal Article] PDE1C negatively regulates growth factor receptor degradation and promotes vascular smooth muscle cell proliferation. (2015)
  • Author(s): Satoh K, Kikuchi N, Kurosawa R, Shimokawa H.
  • Journal Title: Circ Res. Volume: 116 Issue: 7 Pages: 1098-1100
  • DOI: 10.1161/circresaha.115.306139
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Cyclophilin A in Cardiovascular Homeostasis and Diseases (2015)
  • Author(s): Satoh K
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 235 Issue: 1 Pages: 1-15
  • DOI: 10.1620/tjem.235.1
  • NAID: 130004822422
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside. (2014)
  • Author(s): Shimokawa H.
  • Journal Title: Eur Heart J. Volume: 35 Issue: 45 Pages: 3180-3193
  • DOI: 10.1093/eurheartj/ehu427
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Basigin mediates pulmonary hypertension by promoting inflammation and vascular smooth muscle cell proliferation. (2014)
  • Author(s): Satoh K, Satoh T, Kikuchi N, Omura J, Kurosawa R, Suzuki K, Sugimura K, Aoki T, Nochioka K, Tatebe S, Yamamoto S, Miura M, Shimizu T, Ikeda S, Yaoita N, Fukumoto Y, Minami T, Miyata S, Nakamura K, Ito H, Kadomatsu K, Shimokawa H.
  • Journal Title: Circ Res. Volume: 115 Issue: 8 Pages: 738-750
  • DOI: 10.1161/circresaha.115.304563
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vascular function. (2014)
  • Author(s): Shimokawa H, Satoh K.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 11 Pages: 2359-2362
  • DOI: 10.1161/atvbaha.114.304119
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Light and dark of reactive oxygen species for vascular function. (2014)
  • Author(s): Shimokawa H, Satoh K.
  • Journal Title: J Cardiovasc Pharmacol. Volume: 65
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] High-sensitivity C-reactive protein: still need for next-generation biomarkers for remote future cardiovascular events. (2014)
  • Author(s): Satoh K, Shimokawa H.
  • Journal Title: Eur Heart J. Volume: 35 Issue: 27 Pages: 1776-1778
  • DOI: 10.1093/eurheartj/ehu115
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dual roles of vascular-derived reactive oxygen species-With a special reference to hydrogen peroxide and cyclophilin A (2014)
  • Author(s): Kimio Satoh, Shigeo Godo, Hiroki Saito, Budbazar Enkhjargal, Hiroaki Shimokawa
  • Journal Title: Journal of molecular and cellular cardiology Volume: (In press) Pages: 50-56
  • DOI: 10.1016/j.yjmcc.2013.12.022
  • Peer Reviewed / Open Access
• [Journal Article] Globotriaosylceramide induces endothelial dysfunction in Fabry disease. (2014)
  • Author(s): Satoh K.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 1 Pages: 2-4
  • DOI: 10.1161/atvbaha.113.302744
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Crucial role of rho-kinase in pressure overload-induced right ventricular hypertrophy and dysfunction in mice. (2014)
  • Author(s): Ikeda, S., Satoh, K., Kikuchi, N., Miyata, S., Suzuki, K., Omura, J., Shimizu, T., Kobayashi, K., Kobayashi, K., Fukumoto, Y., Sakata, Y., and Shimokawa, H.
  • Journal Title: Arterioscler. Thromb. Vasc Biol. Volume: 34 Issue: 6 Pages: 1260-1271
  • DOI: 10.1161/atvbaha.114.303320
  • Peer Reviewed / Open Access
• [Journal Article] Combination therapy with fasudil and sildenafil ameliorates monocrotaline-induced pulmonary hypertension and survival in rats. (2014)
  • Author(s): Elias-Al-Mamun M, Satoh K, Tanaka S, Shimizu T, Nergui S, Miyata S, Fukumoto Y, Shimokawa H.
  • Journal Title: Circ J. Volume: 78 Pages: 967-976
  • NAID: 130003391036
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Endothelial AMPK regulates blood pressure and coronary flow responses through hyperpolarization mechanism in mice. (2014)
  • Author(s): Enkhjargal B, Godo S, Sawada A, Nergui S, Saito H, Noda K, Satoh K, Shimokawa H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 7 Pages: 1505-1513
  • DOI: 10.1161/atvbaha.114.303735
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Platelets are highly activated in patients of chronic thromboembolic pulmonary hypertension (CTEPH). (2014)
  • Author(s): Yaoita N, Shirakawa R, Fukumoto Y, Sugimura K, Miyata S, Miura Y, Nochioka K, Miura M, Tatebe S, Aoki T, Miyamichi-Yamamoto S, Satoh K, Kimura T, Shimokawa H, Horiuchi H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 34 Issue: 11 Pages: 2486-2494
  • DOI: 10.1161/atvbaha.114.304404
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Enhanced [18F]fluorodeoxyglucose accumulation in the right ventricular free wall predicts long-term prognosis of patients with pulmonary hypertension: a preliminary observational study. (2014)
  • Author(s): Tatebe S, Fukumoto Y, Oikawa-Wakayama M, Sugimura K, Satoh K, Miura Y, Aoki T, Nochioka K, Miura M, Yamamoto S, Tashiro M, Kagaya Y, Shimokawa H.
  • Journal Title: Eur Heart J Cardiovasc Imaging. Volume: 15 Issue: 6 Pages: 666-672
  • DOI: 10.1093/ehjci/jet276
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] OCT imaging for the management of pulmonary hypertension. (2014)
  • Author(s): Dai Z, Fukumoto Y, Tatebe S, Sugimura K, Miura Y, Nochioka K, Aoki T, Miyamichi-Yamamoto S, Yaoita N, Satoh K, Shimokawa H.
  • Journal Title: JACC-Cardiovasc Imaging. Volume: 7 Issue: 8 Pages: 843-845
  • DOI: 10.1016/j.jcmg.2014.01.020
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Visualization of Complete Regression of Pulmonary Arterial Remodeling on Optical Coherence Tomography in a Patient With Pulmonary Arterial Hypertension. (2014)
  • Author(s): Dai Z, Sugimura K, Fukumoto Y, Tatebe S, Miura Y, Nochioka K, Aoki T, Miyamichi-Yamamoto S, Yaoita N, Satoh K, Shimokawa H.
  • Journal Title: Circ J. Volume: 78 Pages: 2771-2773
  • NAID: 130004700253
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Extracorporeal low-energy shock wave therapy exerts anti-inflammatory effects in acute myocardial infarction in rats in vivo. (2014)
  • Author(s): Abe Y, Ito K, Hao K, Shindo T, Ogata T, Kagaya Y, Kurosawa R, Nishimiya K, Satoh K, Miyata S, Kawakami K, Shimokawa H.
  • Journal Title: Circ J. Volume: 78 Pages: 2915-2925
• [Journal Article] Statins exert pleiotropic effects through SmgGD S up-regulation with a resultant Rac l degradation (2013)
  • Author(s): Tanaka S, Fukumoto Y, Nochioka K, Minami T, Kudo S, Shiba N, Takai Y, Williams CL, Liao JK, Shimokawa H
  • Journal Title: Arterioscter Thromz Vasc Biol Volume: (in press) Issue: 7 Pages: 1591-1600
  • DOI: 10.1161/atvbaha.112.300922
  • Peer Reviewed / Open Access
• [Journal Article] Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications and prognostic impact -Multicenter registrystudy of the Japanese Coronary Spasm Association- (2013)
  • Author(s): Takagi Y, Yasuda S, Takahashi J, TsunodaR, Ogata Y, Seki A, Sumiyoshi T, Matsui M, Goto T, Tanabe Y, Sueda S, Sato T, Ogawa S, Kubo N, Momomura S, Ogawa H, Shimokawa H
  • Journal Title: Eur Heart J Volume: 34 Issue: 4 Pages: 258-267
  • DOI: 10.1093/eurheartj/ehs199
  • Peer Reviewed
• [Journal Article] Plasma Cyclophilin A Is a Novel Biomarker for Coronary Artery Disease (2013)
  • Author(s): Satoh K, Fukumoto Y, Sugimura K, Miura Y, Aoki T, Nochioka K, Tatebe S, Miyamichi-Yamamoto S, Shimizu T, Osaki S,Takagi Y, Tsuburaya R, Ito Y, Matsumoto Y, Nakayama M, Takeda M, Takahashi J, Ito K, Yasuda S, Shimokawa H
  • Journal Title: Circulation Journal Volume: 77 Issue: 2 Pages: 447-455
  • DOI: 10.1253/circj.CJ-12-0805
  • NAID: 10031138924
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Dipeptidyl Peptidase-4 Inhibitors (2013)
  • Author(s): 佐藤公雄 (Kimio Satoh)
  • Journal Title: Circulation Journal Volume: 77 Issue: 5 Pages: 1156-1157
  • DOI: 10.1253/circj.CJ-13-0064
  • NAID: 10031151374
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Presentation] William Harvey Lecture: Importance of coronary vasomotion abnormalities –From bench to bedside- (2014)
  • Author(s): Shimokawa H.
  • Organizer: European Society Congress 2014
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2014-08-30 – 2014-09-03
  • Invited
• [Presentation] Asian Lecture in Vascular Biology: Light and dark of reactive oxygen species for vascular function. (2014)
  • Author(s): Shimokawa H.
  • Organizer: Pharmacology & Pgysiology International Scientific Congress 2014/Asian Society of Vascular Bilogy Meeting
  • Place of Presentation: Kuala Lumpur, Malaysia
  • Year and Date: 2014-08-22 – 2014-08-24
  • Invited
• [Presentation] Symposium: Coronary vasospasm: what do we know and why is it important?: Pathogenesis of vasospastic angina. (2014)
  • Author(s): Shimokawa H.
  • Organizer: 2014 World Congress of Cardiology
  • Place of Presentation: Melbourne, Australia
  • Year and Date: 2014-05-04 – 2014-05-07
  • Invited
• [Book] 「循環器内科」特集/循環器疾患と分子遺伝学 肺高血圧症の分子基盤 (2015)
  • Author(s): 佐藤 公雄、下川 宏明.
  • Total Pages: 8
  • Publisher: 科学評論社
• [Book] 『酸化ストレスの医学 改訂第２版』(2014年8月) 心疾患と酸化ストレス (2014)
  • Author(s): 佐藤 公雄、下川 宏明.
  • Total Pages: 7
  • Publisher: 診断と治療社
• [Book] 日本医師会雑誌 141 (2013)
  • Author(s): 下川宏明
  • Publisher: 日本医師会
• [Remarks] 東北大学循環器内科
  • URL: http://www.cardio.med.tohoku.ac.jp/
• [Patent(Industrial Property Rights)] サイクロフィリンＡによる心血管疾患の検査方法 (2014)
  • Inventor(s): 下川宏明、佐藤公雄 (国立大学法人東北大学)
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄 (国立大学法人東北大学)
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-239615
  • Filing Date: 2014-10-30
  • Acquisition Date: 2015-02-10
• [Patent(Industrial Property Rights)] サイクロフィリンＡによる心血管疾患の検査方法 (2013)
  • Inventor(s): 下川宏明、佐藤公雄 (国立大学法人東北大学)
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄 (国立大学法人東北大学)
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-10-29
  • Acquisition Date: 2015-02-10
  • Overseas
• [Patent(Industrial Property Rights)] 「サイクロフィリンＡによる心血管疾患の検査方法」 (2013)
  • Inventor(s): 下川宏明、佐藤公雄 (国立大学法人東北大学)
  • Industrial Property Rights Holder: 東北大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-10-29
  • Overseas