New treatment for pulmonary arterial hypertension targeting on inflammation-dedifferentiation pathway

• Project/Area Number: 15K09688
• 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): 田中 利男 三重大学, 医学系研究科, 教授 (00135443) ; 丸山 一男 三重大学, 医学系研究科, 教授 (20181828) ; 西村 有平 三重大学, 医学系研究科, 教授 (30303720) ; 澤田 博文 三重大学, 医学系研究科, 講師 (30362354)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺高血圧 / 肺動脈性肺高血圧 / 治療 / 病態 / 炎症 / 血管平滑筋 / 動物モデル / 平滑筋 / エンドセリン / 血管生物学

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is an intractable disorder, which is idiopathic or occurs secondarily to congenital heart diseases, collagen diseases or other conditions. Development of new therapies on the basis of the well-defined therapeutic targets is essential for overcoming this condition. We recently uncovered the role of dedifferentiated smooth muscle cells and inflammatory cells in the development of a human PAH-like rat models. We therefore searched therapeutic targets on the basis of the differentially expressed genes related to dedifferentiation and inflammation in such models operating under the endothelin receptor blockade. We found that endothelin receptor blockade reversed pulmonary vascular diseases in the early treatment, which was associated with two differentially-expressed genes. We abrogated one unverified target in this model by receptor antagonists. We could found one of the compound ameliorated pulmonary vascular diseases in this condition.

Research Products

• [Journal Article] Association of Severity of Coronary Artery Aneurysms in Patients With Kawasaki Disease and Risk of Later Coronary Events. (2018)
  • Author(s): Miura M, Kobayashi T, Kaneko T, Ayusawa M, Mitani Y, Sato S, Yamamura K.
  • Journal Title: JAMA Pediatr. Volume: 5
  • Peer Reviewed
• [Journal Article] Genetic mutation analysis in Japanese patients with non-syndromic congenital heart disease. (2016)
  • Author(s): Morisaki T, Yoshida A, Morisaki H, Nakaji M, Kinano M, Kim K, Sagawa K, Ishikawa S, Satokata I, Mitani Y, Hamaoka K, Echigo S, Shiraishi I, and Kato H.
  • Journal Title: J Hum Genet Volume: 61(2) Issue: 2 Pages: 157-162
  • DOI: 10.1038/jhg.2015.126
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] Sarpogrelate hydrochloride, a serotonin 5HT2A receptor antagonist, ameliorates the development of chronic hypoxic pulmonary hypertension in rats (2015)
  • Author(s): Zhang E, Maruyama J, et al.
  • Journal Title: J Anesth Volume: 29 Issue: 5 Pages: 715-723
  • DOI: 10.1007/s00540-015-2015-y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aiming for Zero Deaths: Prevention of Sudden Cardiac Death in Schools – Statement From the AED Committee of the Japanese Circulation Society – (2015)
  • Author(s): Mitamura H, Iwami T, Mitani Y, Takeda S, Takatsuki S.
  • Journal Title: Circulation Journal Volume: 79 Issue: 7 Pages: 1398-1401
  • DOI: 10.1253/circj.CJ-15-0453
  • NAID: 130005083957
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Early Detection of Pulmonary Arterial Hypertension in Apparently Healthy Children by Mandatory School Electrocardiography Screening: A Japanese Nationwide Survey (2018)
  • Author(s): Yoshihide Mitani
  • Organizer: World Symposium on Pulmonary Hypertension
  • Int'l Joint Research / Invited
• [Presentation] The use of EKG as a screening tool (2017)
  • Author(s): Yoshihide Mitani .
  • Organizer: 10th International conference of neonatal & Childhood Pulmonary Vascular Disease
  • Int'l Joint Research / Invited
• [Presentation] Lung Biopsy Findings in Children with Severe Pulmonary Hypertension Which is Associated with but Unexplained by Coexisting Congenital Systemic to Pulmonary Shunt: Implications into the Role of Acute Vasodilator Testing in Operability (2017)
  • Author(s): Hirofumi Sawada, Hiroyuki Ohashi, Shoichiro Ohtsuki, Noriko Yodoya, Hidetoshi Hayakawa , Takeshi Konuma, Hideto Shimpo, Kyoko Imanaka-Yoshida Kazuo Maruyama , Masahiro Hirayama and Yoshihide Mitani .
  • Organizer: American Thoracic Society
  • Int'l Joint Research
• [Presentation] Differentially Expressed Genes in Early and Late Treatment for Occlusive Pulmonary Vasculopathy in Sugen/hypoxia Models: Molecular Basis for Early Treatment (2017)
  • Author(s): Yoshihide Mitani, Hirofumi Sawada, Tsutomu Shinohara, Shoichiro Otsuki, Noriko Yodoya, Hiroyuki Ohashi, Taichi Kato, Erquan Zhang, Yuhei Nishimura, Toshio Tanaka, Kazuo Maruyama, Masahiro Hirayama.
  • Organizer: American Heart Association
  • Int'l Joint Research
• [Presentation] Fundamental insight into pulmonary vascular disease: Perspectives from pediatric PAH (2017)
  • Author(s): Yoshihide Mitani
  • Organizer: The 8th Takao Symposium
  • Int'l Joint Research / Invited
• [Presentation] 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, USA
  • Year and Date: 2015-11-09
  • Int'l Joint Research / 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: Prague,Czech Republic
  • Year and Date: 2015-05-20
  • Int'l Joint Research / Invited
• [Presentation] ECG screening and AED program for school children: The Japanese experience (2015)
  • Author(s): Mitani Y
  • Organizer: Association for European Pediatric and Congenital Cardiology
  • Place of Presentation: Prague,Czech Republic
  • Year and Date: 2015-05-20
  • Int'l Joint Research / Invited
• [Book] Diagnostis and Treatment of Pulmonary Hypertension-From Bench to Bedside (2017)
  • Author(s): Mitani Y
  • Total Pages: 236
  • Publisher: Springer
• [Book] Eisenmenger症候群ー小児から成人までー (2017)
  • Author(s): 三谷義英
  • Total Pages: 159
  • Publisher: 医薬ジャーナル