Functional analysis of novel cardiovascular protective factor

• Project/Area Number: 16K15198
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Tohoku University
• Principal Investigator: Shimokawa Hiroaki 東北大学, 医学系研究科, 教授 (00235681)
• Co-Investigator(Kenkyū-buntansha): 佐藤 公雄 東北大学, 高度教養教育・学生支援機構, 准教授 (80436120)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 循環器・高血圧 / 大動脈瘤 / 医歯薬学 / 内科系臨床医学 / 循環器内科学 / 分子血管学 / 臨床応用研究 / 基礎医学 / 薬理学一般 / 心血管・血液

Outline of Final Research Achievements

We conducted basic and clinical studies on the SmgGDS-mediated protective function of cardiovascular system. In particular, in order to investigate whether SmgGDS secreted extracellularly by statin stimulation has protective effects on vascular endothelium and cardiovascular system, we developed genetically-deficient mice and overexpressing mice in our department. Additionally, we performed in vitro studies on the role of intracellular SmgGDS which promoted Rac1 degradation while extracellular SmgGDS had an important role in suppressing fibroblast proliferation and MMP activities. Finally, in vivo study demonstrated that SmgGDS inhibits the development of thoracic aortic aneurysms and resulting aortic rupture.

Research Products

• [Journal Article] Selenoprotein P promotes vascular smooth muscle cell proliferation and pulmonary hypertension -A possible novel therapeutic target- (2018)
  • Author(s): Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Md. Elias Al-Mamun, Mohammad Abdul Hai Siddique, Omura J, Satoh T, Nogi M, Sunamura S, Miyata S, Shimokawa H.
  • Journal Title: Circulation Volume: ―
  • Peer Reviewed / Open Access
• [Journal Article] Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension. (2018)
  • Author(s): Kozu K, Sugimura K, Aoki T, Tatebe S, Yamamoto S, Yaoita N, Shimizu T, Nochioka K, Sato H, Konno R, Satoh K, Miyata S, Shimokawa H.
  • Journal Title: Heart Vessels. Volume: in press Issue: 8 Pages: 939-947
  • DOI: 10.1007/s00380-018-1140-6
  • Peer Reviewed / Open Access
• [Journal Article] Shrinking basic cardiovascular research in Japan: A tip of the iceberg. (2017)
  • Author(s): Shimokawa H, Kikuchi N, Satoh K.
  • Journal Title: Circ Res. Volume: 121 Issue: 4 Pages: 331-334
  • DOI: 10.1161/circresaha.117.310845
  • Peer Reviewed / Open Access
• [Journal Article] European Society of Cardiology (ESC) Annual Congress Report From Barcelona 2017 (2017)
  • Author(s): Satoh K, Takahashi J, Matsumoto Y, Tatebe S, Aoki T, Kikuchi Y, Hao K, Ohyama K, Nogi M, Suda A, Kasahara S, Sato K, Ichijo S, Shimokawa H.
  • Journal Title: Circulation Journal Volume: 81 Issue: 12 Pages: 1758-1763
  • DOI: 10.1253/circj.CJ-17-1103
  • NAID: 130006219237
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive evaluation of the effectiveness and safety of balloon pulmonary angioplasty for inoperable chronic thrombo-embolic pulmonary hypertension: long-term effects and procedure-related complications. (2017)
  • Author(s): Aoki T, Sugimura K, Tatebe S, Miura M, Yamamoto S, Yaoita N, Suzuki H, Sato H, Kozu K, Konno R, Miyata S, Nochioka K, Satoh K, Shimokawa H.
  • Journal Title: Eur Heart J. Volume: 7 Issue: 42 Pages: 3152-3159
  • DOI: 10.1093/eurheartj/ehx530
  • Peer Reviewed / Open Access
• [Journal Article] The Efficacy of a Genetic Analysis of the <i>BMPR2</i> Gene in a Patient with Severe Pulmonary Arterial Hypertension and an Atrial Septal Defect Treated with Bilateral Lung Transplantation (2017)
  • Author(s): Tatebe S, Sugimura K, Aoki T, Yamamoto S, Yaoita N, Suzuki H, Sato H, Kozu K, Konno R, Satoh K, Fukuda K, Adachi O, Saito R, Nakanishi N, Morisaki H, Oyama K, Saiki Y, Okada Y, Shimokawa H.
  • Journal Title: Internal Medicine Volume: 56 Issue: 23 Pages: 3193-3197
  • DOI: 10.2169/internalmedicine.8686-16
  • NAID: 130006235510
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] SmgGDS as a crucial mediator of the inhibitory effects of statins on cardiac hypertrophy and fibrosis -Novel mechanism of the pleiotropic effects of statins- (2016)
  • Author(s): Kudo S, Satoh K, Nogi M, Suzuki K, Sunamura S, Omura J, Kikuchi N, Kurosawa R, Satoh T, Minami T, Ikeda S, Miyata S, Shimokawa H.
  • Journal Title: Hypertension Volume: 67 Issue: 5 Pages: 878-889
  • DOI: 10.1161/hypertensionaha.115.07089
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Statins up-regulate SmgGDS through β1-integrin/Akt1 pathway in endothelial cells. (2016)
  • Author(s): Minami T, Satoh K, Nogi M, Kudo S, Miyata S, Tanaka S, Shimokawa H. Statins up-regulate SmgGDS through β1-integrin/Akt1 pathway in endothelial cells.
  • Journal Title: Cardiovasc Res. Volume: 109 Issue: 1 Pages: 151-161
  • DOI: 10.1093/cvr/cvv253
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] RhoA/Rho-kinase in the cardiovascular system. (2016)
  • Author(s): Shimokawa H, Sunamura S, Satoh K.
  • Journal Title: Circ Res. Volume: 118 Issue: 2 Pages: 352-366
  • DOI: 10.1161/circresaha.115.306532
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Selenoprotein P promotes the development of pulmonary arterial hypertension-A Possible Novel Therapeutic Target- (2018)
  • Author(s): Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Elias-Al-Mamun M, Abdul Hai Siddique M, Omura J, Satoh T, Nogi M, Sunamura S, Miyata S, Saito Y, Hoshikawa Y, Okada Y, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Presentation] ADAMTS8 Promotes the Development of pulmonary arterial hypertension and right ventricular failure-A possible novel therapeutic target- (2018)
  • Author(s): Satoh K, Omura J, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Sunamura S, Ohtsuki T, Elias-Al-Mamun M, Abdul Hai Siddique M, Yaoita N, Miyata S, Hoshikawa Y, Okada Y, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Presentation] Identification of celastramycin as a novel therapeutic agent for pulmonary arterial hypertension -High-throughput screening of 5,562 compounds- (2018)
  • Author(s): Kurosawa R, Satoh K, Kikuchi N, Satoh T, Omura J, Nogi M, Sunamura S, Ohtsuki T, Yaoita N, Abdul Hai Siddique M, Elias-Al-Mamun M, Shimizu T, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Presentation] Different roles of myocardial ROCK1 and ROCK2 in response to chronic pressure-overload in mice. (2018)
  • Author(s): Sunamura S, Satoh K, Shimizu T, Suzuki K, Ikeda S, Kudo S, Omura J, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Ohtsuki T, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Presentation] Identification of Emetine as a Novel Therapeutic Agent for Pulmonary Hypertension in Rats -High-throughput Screening of 5,562 Compounds- (2018)
  • Author(s): Abdul Hai Siddique M, Satoh K, Kurosawa R, Elias-Al-Mamun M, Kikuchi N, Omura J, Satoh T, Nogi M, Sunamura S, Shimokawa H.
  • Organizer: World Symposium on Pulmonary Hypertension
  • Int'l Joint Research
• [Book] 特集/SGLT2心腎連関 解説 Cyclophilin A（2017年10月号） (2017)
  • Author(s): 佐藤 公雄、下川 宏明.
  • Total Pages: 7
  • Publisher: 科学評論社
• [Remarks] 東北大学循環器内科ホームページ
  • URL: http://www.cardio.med.tohoku.ac.jp/
• [Patent(Industrial Property Rights)] セレノプロテインＰ活性阻害作用を有する成分を含有する、肺高血圧症の予防又は治療剤 (2017)
  • Inventor(s): 下川宏明、佐藤公雄、菊地順裕
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄、菊地順裕
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] 生薬成分を含む肺高血圧症の予防又は治療剤 (2017)
  • Inventor(s): 下川宏明, 佐藤公雄, 黒澤亮
  • Industrial Property Rights Holder: 下川宏明, 佐藤公雄, 黒澤亮
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] 不飽和複素５員環含有化合物を含有する肺高血圧症の予防又は治療剤 (2017)
  • Inventor(s): 下川宏明, 佐藤公雄, 黒澤亮
  • Industrial Property Rights Holder: 下川宏明, 佐藤公雄, 黒澤亮
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] PPARαアゴニストを含有する、肺高血圧症の予防又は治療剤 (2017)
  • Inventor(s): 下川宏明、佐藤公雄、佐藤大樹
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄、佐藤大樹
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • 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 (2016)
  • Inventor(s): 下川宏明、佐藤公雄
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016
  • Acquisition Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] 肺高血圧症の検査方法 (2016)
  • Inventor(s): 下川宏明、佐藤公雄、菊地順裕
  • Industrial Property Rights Holder: 下川宏明、佐藤公雄、菊地順裕
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016
  • Acquisition Date: 2017