Molecular mechanisms involved in the pathogenesis of occlusive pulmonary vasculopathy

• Project/Area Number: 24591574
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Mie University
• Principal Investigator: MITANI Yoshihide 三重大学, 医学部附属病院, 准教授 (60273380)
• Co-Investigator(Kenkyū-buntansha): SAWADA Hirofumi 三重大学, 医学(系)研究科(研究院), 講師 (30362354) ; MARUYAMA Kazuo 三重大学, 医学(系)研究科(研究院), 教授 (20181828)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 小児科学 / 小児循環器学 / 肺高血圧 / 動物モデル / ラットモデル / 増悪 / 退縮 / 細胞死

Outline of Final Research Achievements

Project 1-Phenotypically Modulated Smooth Muscle Cells and Related Inflammation in the Development of Experimental Obstructive Pulmonary Vasculopathy in Rats -: We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). We concluded that phenotypically modulated SMCs and related inflammation are associated with the progression of experimental obstructive PVD.
Project 2-Macitentan reverses early obstructive pulmonary vasculopathy in rats-
We test the hypothesis that a novel endothelin receptor antagonist macitentan reverses the early and/or late stages of occlusive pulmonary vascular disease (PVD) in rats. In conclusion, macitentan reversed early but not late obstructive PVD in rats. This reversal was associated with the suppression of survivin-related resistance to apoptosis and proliferation of cells in PVD.

Research Products

• [Journal Article] Potential Contribution of Phenotypically Modulated Smooth Muscle Cells and Related Inflammation in the Development of Experimental Obstructive Pulmonary Vasculopathy in Rats. (2015)
  • Author(s): Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Zhang E, Imanaka-Yoshida K, Shimpo H, Maruyama K, Komada Y, Mitani Y.
  • Journal Title: PLoS One. Volume: 10 Issue: 2 Pages: 0118655-0118655
  • DOI: 10.1371/journal.pone.0118655
  • Peer Reviewed / Open Access
• [Journal Article] Macitentan reverses early obstructive pulmonary vasculopathy in rats: early intervention in overcoming the survivin-mediated resistance to apoptosis. (2015)
  • Author(s): Shinohara T, Sawada H, Otsuki S, Yodoya N, Kato T, Ohashi H, Zhang E, Saitoh S, Shimpo H, Maruyama K, Komada Y, Mitani Y.
  • Journal Title: Am J Physiol Lung Cell Mol Physiol. Volume: 308(6) Issue: 6 Pages: L523-L538
  • DOI: 10.1152/ajplung.00129.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effect of thrombomodulin on the development of monocrotaline-induced pulmonary hypertension. (2014)
  • Author(s): Yamada Y, Maruyama J, Zhang E, Maruyama K. et al
  • Journal Title: J Anesth Volume: 28(1) Issue: 1 Pages: 26-33
  • DOI: 10.1007/s00540-013-1663-z
  • Peer Reviewed
• [Journal Article] Circumstances and Outcomes of Out-Of-Hospital Cardiac Arrest in Elementary and Middle School Students in the Era of Public-Access Defibrillation: Implications for Emergency Preparedness in Schools (2014)
  • Author(s): Mitani Y, Ohta K, Ichida F, Nii M, Arakaki Y, Ushinohama H, Takahashi T, Ohashi H, Yodoya N, Fujii E, Ishikura K, Tateno S, Sato S, Suzuki T, Higaki T, Iwamoto M, Yoshinaga M, Nagashima M, Sumitomo N
  • Journal Title: Circulation J Volume: 78(3) Pages: 701-707
  • NAID: 130003391007
  • Peer Reviewed
• [Journal Article] Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. (2014)
  • Author(s): Sawada H, Saito T, Nickel NP, Alastalo TP, Glotzbach JP, Chan R, Haghighat L, Fuchs G, Januszyk M, Cao A, Lai YJ, Perez Vde J, Kim YM, Wang L, Chen PI, Spiekerkoetter E, Mitani Y, Gurtner GC, Sarnow P, Rabinovitch M.
  • Journal Title: Journal of Experimental Medicine Volume: 211 Issue: 2 Pages: 263-280
  • DOI: 10.1084/jem.20111741
  • Peer Reviewed
• [Journal Article] Public access defibrillation improved the outcome after out-of-hospital cardiac arrest in school-age children: a nationwide, population-based, Utstein registry study in Japan (2013)
  • Author(s): Mitani Y, Ohta K, Yodoya N, Otsuki S, Ohashi H, Sawada H, Nagashima M, Sumitomo N, Komada Y.
  • Journal Title: Europace Volume: 15 Issue: 9 Pages: 1259-66
  • DOI: 10.1093/europace/eut053
  • Peer Reviewed
• [Journal Article] 小児期肺高血圧と先天性心疾患に伴う肺血管病変：An update (2013)
  • Author(s): 三谷義英
  • Journal Title: 日本小児循環器学会雑誌 Volume: 29(1) Pages: 17-26
  • Peer Reviewed
• [Journal Article] 長期経過した川崎病既往児に対する対応 (2012)
  • Author(s): 三谷義英
  • Journal Title: 小児科臨床 Volume: 65 Pages: 1611-1619
• [Journal Article] 肺動脈性高血圧の最近の知見：血管医学の新しい研究領域 (2012)
  • Author(s): 三谷義英
  • Journal Title: 血管 Volume: 35 Pages: 105-114
  • NAID: 10031128076
• [Journal Article] 学校心停止とAED (2012)
  • Author(s): 三谷義英
  • Journal Title: 救急医学 Volume: 36 Pages: 1668-1671
• [Presentation] Ask the Experts: What is the Cellular Target in Occlusive Pulmonary Vasculopathy ?: New Insights Immature Smooth Muscle Cells (2015)
  • Author(s): Mitani Y
  • Organizer: American Heart Association
  • Place of Presentation: Orland, US
  • Year and Date: 2015-11-08 – 2015-11-11
  • Invited
• [Presentation] Macitentan Reverses Early Obstructive Pulmonary Vasculopathy in Rats: Early Intervention in Overcoming the Survivin-mediated Resistance to Apoptosis (2015)
  • Author(s): Shinohara T., Sawada H., Otsuki S., Yodoya N., Kato T., Ohashi H., Zhang E., Saitoh S., Shimpo H., Maruyama K., Komada Y., Mitani Y.
  • Organizer: Association for European Pediatric and Congenital Cardiology
  • Place of Presentation: Peague, Czech Republic
  • Year and Date: 2015-05-20 – 2015-05-23
  • Invited
• [Presentation] Phenotypic Modulation of Smooth Muscle Cells and Related Inflammation in the Development of Experimental Obstructive Pulmonary Vasculopathy in Rats. (2013)
  • Author(s): Otsuki S, Sawada H, Yodoya N, Shinohara T, Kato T, Ohashi H, Zhang E, Yoshida-Imanaka K, Shimpo H, Maruyama K, Komada Y, Mitani Y.
  • Organizer: American Heart Association
  • Place of Presentation: 米国
  • Invited
• [Presentation] Early detection of pediatric idiopathic pulmonary arterial hypertension by school electrocardiography screening: a nationwide survey in Japan. (2013)
  • Author(s): Sawada H, Mitani Y, Nakayama T, Fukushima H, Kogaki S, Igarashi T, Ichida F, Ono Y, Nakanishi T, Doi S, Ishikawa S, Matsushima M, Yamada O, Saji T.
  • Organizer: American Heart Association
  • Place of Presentation: 米国
• [Presentation] Medical treatment of pulmonary arterial hypertension and pulmonary vascular disease associated with congenital heart disease (2013)
  • Author(s): Mitani Y
  • Organizer: The 21th meeting of the Asian Society for Cardiovascular and Thoracic Surgery
  • Place of Presentation: Kobe
  • Invited
• [Presentation] Reduced BMPR-II Induces GM-CSF Translation and Macrophage Recruitement in Human and Mice, Exacerbating Pulmonary Hypertension. (2013)
  • Author(s): Hirofumi Sawada, Yoshihide Mitani, Noriko Yodoya, Shoichiro Otsuki1, Hiroyuki Ohashi, Kazuo Maruyama, Yoshihiro Komada, Marlene Rabinovitch.
  • Organizer: 第２回日本肺循環学会
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] Bosentan ameliorates pulmonary hypertension in mice by modulating stem cell kinetics and related gene expression: a new therapeutic target. (2013)
  • Author(s): Kato T, Mitani Y
  • Organizer: The 77th Scientific meetig of the Japanese Circulation Society
  • Place of Presentation: Yokohama
  • Invited
• [Presentation] Medical treatment of pulmonary arterial hypertension and pulmonary vascular disease associated with congenital heart disease. (2013)
  • Author(s): Mitani Y
  • Organizer: The 21th meeting of the Asian Society for Cardiovascular and Thoracic Surgery
  • Place of Presentation: Kobe
  • Invited
• [Presentation] Pre-event Course of Culprit Lesions in Acute Coronary Syndrome in Adults with a History of Kawasaki Disease: A Nationwide Survey (2013)
  • Author(s): Yoshihide Mitani, Etsuko Tsuda, Mamoru Ayusawa, Touru Kobayashi, Fukiko Ichida, Masaki Matsushima, Takashi Higaki, Kenji Suda, Hiroyoshi Yokoi, Kenji Hamaoka
  • Organizer: The 77th Scientific meetig of the Japanese Circulation Society
  • Place of Presentation: Yokohama
• [Presentation] Role of endogenous bone marrow-derived stem cells and its pharmacological modulation in pulmonary arterial hypertension in mice: a new mechanism of action in bosentan therapy. (2012)
  • Author(s): Taichi Kato, Hirofumi Sawada, Hiroyuki Ohashi, Shoichiro Otsuki, Noriko Yodoya, Hideto Shimpo, Yoshihiro Komada, Yoshihide Mitani.
  • Organizer: American Heart Association
  • Place of Presentation: LA
• [Presentation] Public access defibrillation improved the outcome after out-of-hospital cardiac arrests in school-age children: a nationwide, population-based, Utstein registry study in Japan (2012)
  • Author(s): Yoshihide Mitani, Kunio Ohta, Noriko Yodoya, Shoichiro Otsuki, Hiroyuki Ohashi, Hirofumi Sawada, Masami Nagashima, Naokata Sumitomo, Yoshihiro Komada,
  • Organizer: American Heart Association
  • Place of Presentation: LA