Development of a novel diagnostic and prognostic biomarker for pulmonary arterial hypertension

• Project/Area Number: 18K08094
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Tohoku University
• Principal Investigator: Kikuchi Nobuhiro 東北大学, 医学系研究科, 大学院非常勤講師 (70816454)
• 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): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肺動脈性肺高血圧症 / バイオマーカー / セレノプロテインP / 肺高血圧症

Outline of Final Research Achievements

Pulmonary arterial hypertension (PAH) is a rare disease without a specific biomarker for its diagnosis. We have recently demonstrated that gene expression of selenoprotein P (SeP) in the lung is markedly up-regulated in PAH patients and plays crucial roles in the pathogenesis of the disorder. In this study, we examined whether serum levels of SeP could be a useful biomarker for the disease. PAH patients showed significantly higher levels of serum SeP compared with controls. Higher SeP levels were associated with the composite endpoint of all-cause death and lung transplantation in PAH patients. Importantly, absolute changes in SeP levels in PAH patients significantly correlated with those of some important hemodynamic parameters. Furthermore, the increases in SeP levels during follow-up predicted the poor outcome of PAH patients. These results indicate that serum SeP levels are a novel biomarker for diagnosis and assessment of treatment efficacy and long-term prognosis in PAH patients.

Academic Significance and Societal Importance of the Research Achievements

肺動脈性肺高血圧症は、現時点で根本的な治療法が肺移植のみに限られる重篤な難病である。その非特異的症状のため早期診断が難しく、現在までに実用化された疾患特異的バイオマーカーは存在しない。本研究で明らかになったセレノプロテインPを本疾患のバイオマーカーとして実用化することができれば、これまで入院の上心臓カテーテル検査などの侵襲的検査を行うことでしか診断や治療効果判定が出来なかった本疾患について、より簡便な非侵襲的スクリーニングが可能となり、診断後も定期的に必要であった入院検査を安全に減らすことができれば、患者負担を減らし適切な治療法の選択につながることが期待される。

Research Products

• [Journal Article] Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A). (2021)
  • Author(s): Kurosawa R, Satoh K, Nakata T, Shindo T, Kikuchi N, Satoh T, Siddique MAH, Omura J, Sunamura S, Nogi M, Takeuchi Y, Miyata S, Shimokawa H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 41 Issue: 3 Pages: 1205-1217
  • DOI: 10.1161/atvbaha.120.315731
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension (2020)
  • Author(s): Yaoita N, Satoh K, Tatebe S, Yasuda S, Shimokawa H et al.
  • Journal Title: J Am Heart Assoc . Volume: 9 Issue: 21 Pages: 1-12
  • DOI: 10.1161/jaha.120.015902
  • Peer Reviewed / Open Access
• [Journal Article] PIM1 (Provirus Integration Site For Moloney Murine Leukemia Virus) as a Novel Biomarker and Therapeutic Target in Pulmonary Arterial Hypertension (2020)
  • Author(s): Satoh K, Kikuchi N, Shimokawa H.
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 3 Pages: 500-502
  • DOI: 10.1161/atvbaha.120.313975
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic and Prognostic Significance of Serum Levels of SeP (Selenoprotein P) in Patients With Pulmonary Hypertension (2019)
  • Author(s): Nobuhiro Kikuchi, Kimio Satoh, Taijyu Satoh, Nobuhiro Yaoita, Mohammad Abdul Hai Siddique, Junichi Omura, Ryo Kurosawa, Masamichi Nogi, Shinichiro Sunamura, Satoshi Miyata, Hirofumi Misu, Yoshiro Saito, Hiroaki Shimokawa
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 39 Issue: 12 Pages: 2553-2562
  • DOI: 10.1161/atvbaha.119.313267
  • Peer Reviewed / Open Access
• [Journal Article] Response by Kikuchi et al regarding article, "selenoprotein P promotes the development of pulmonary arterial hypertension: a possible novel therapeutic target" (2019)
  • Author(s): Kikuchi N, Satoh K, Saito Y, Shimokawa H.
  • Journal Title: Circulation Volume: 139 Issue: 5 Pages: 724-725
  • DOI: 10.1161/circulationaha.118.038479
  • Peer Reviewed / Open Access
• [Journal Article] Checkpoint kinase 1 promotes the development of pulmonary arterial hypertension (2019)
  • Author(s): Satoh K, Kikuchi N, Kurosawa R, Shimokawa H
  • Journal Title: Arterioscler Thromb Vasc Biol Volume: 39 Issue: 8 Pages: 1504-1506
  • DOI: 10.1161/atvbaha.119.312969
  • Peer Reviewed / Open Access
• [Journal Article] ADAMTS8 promotes the development of pulmonary arterial hypertension and right ventricular failure: a possible novel therapeutic target (2019)
  • Author(s): Omura J, Satoh K, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Ohtsuki T, Elias-Al-Mamun M, Siddique MAH, Yaoita N, Sunamura S, Miyata S, Hoshikawa Y, Okada Y, Shimokawa H
  • Journal Title: Circ Res Volume: 125 Issue: 10 Pages: 884-906
  • DOI: 10.1161/circresaha.119.315398
  • Peer Reviewed / Open Access
• [Journal Article] Identification of celastramycin as a novel therapeutic agent for pulmonary arterial hypertension: high-throughput screening of 5,562 compounds (2019)
  • Author(s): Kurosawa R, Satoh K, Kikuchi N, Kikuchi H, Saigusa D, Elias-Al-Mamun M, Siddique MAH, Omura J, Satoh T, Sunamura S, Nogi M, Numano K, Miyata S, Uruno A, Kano K, Matsumoto Y, Doi T, Aoki J, Oshima Y, Yamamoto M, Shimokawa H
  • Journal Title: Circ Res Volume: 125 Issue: 3 Pages: 309-327
  • DOI: 10.1161/circresaha.119.315229
  • Peer Reviewed / Open Access
• [Journal Article] Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension. (2018)
  • Author(s): Kikuchi N, Satoh K, Kurosawa R, Yaoita N, Elias-Al-Mamun M, Siddique MAH, Omura J, Satoh T, Nogi M, Sunamura S, Miyata S, Saito Y, Hoshikawa Y, Okada Y, Shimokawa H.
  • Journal Title: Circulation Volume: 138 Issue: 6 Pages: 600-623
  • DOI: 10.1161/circulationaha.117.033113
  • Peer Reviewed / Open Access
• [Presentation] Diagnostic and prognostic significance of serum levels of selenoprotein P in patients with pulmonary arterial hypertension (2019)
  • Author(s): Nobuhiro Kikuchi
  • Organizer: アメリカ心臓協会学術集会
  • Int'l Joint Research
• [Presentation] Selenoprotein P and mitochondrial dysfunction in PAH (2019)
  • Author(s): Nobuhiro Kikuchi
  • Organizer: 13th PVRI Annual World Congress on PVD
  • Int'l Joint Research / Invited
• [Presentation] 新規病因蛋白セレノプロテインPによる肺高血圧症 促進機構の解明 (2019)
  • Author(s): 菊地 順裕
  • Organizer: 第60回 日本脈管学会総会
  • Invited
• [Presentation] 新規病因蛋白セレノプロテインPによる肺高血圧症促進機構の解明と治療標的、バイオマーカーとしての臨床応用 (2019)
  • Author(s): 菊地 順裕
  • Organizer: 第4回 日本肺高血圧・肺循環学会学術集会
  • Invited
• [Presentation] Identifications of novel molecular mechanisms and therapeutic targets of pulmonary arterial hypertension (2019)
  • Author(s): 菊地 順裕
  • Organizer: 第83回 日本循環器学会学術集会
  • Invited
• [Presentation] Identifications of Novel Molecular Mechanisms and Therapeutic Targets of Pulmonary Arterial Hypertension. (2019)
  • Author(s): Nobuhiro Kikuchi
  • Organizer: 第83回 日本循環器学会学術集会
  • Invited
• [Presentation] Diagnostic and Prognostic Significance of Serum Levels of Selenoprotein P in Patients with Pulmonary Arterial Hypertension. (2019)
  • Author(s): Nobuhiro Kikuchi
  • Organizer: 第83回 日本循環器学会学術集会
• [Presentation] Selenoprotein P and mitochondrial dysfunction in PAH. (2019)
  • Author(s): Nobuhiro Kikuchi
  • Organizer: 13th PVRI Annual World Congress on PVD
  • Int'l Joint Research / Invited
• [Presentation] Prognostic Impacts of Serum Levels of Selenoprotein P in Patients with Pulmonary Arterial Hypertension. (2018)
  • Author(s): Nobuhiro Kikuchi
  • Organizer: アメリカ心臓協会年次学術集会
  • Int'l Joint Research
• [Presentation] 新規病因蛋白セレノプロテインPによる肺高血圧症促進機構. (2018)
  • Author(s): 菊地 順裕
  • Organizer: 第3回日本肺高血圧・肺循環学会学術集会
  • Invited