Development of a treatment for pulmonary arterial hypertension focusing on inflammatory endothelial dysfunction

• Project/Area Number: 17K16033
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: Inagaki Tadakatsu 国立研究開発法人国立循環器病研究センター, 研究所, 研究員 (20638366)
• Research Collaborator: Masaki Takeshi ; Mori Hiroyoshi ; Fukushima Yasue
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肺動脈性肺高血圧症 / 肺血管リモデリング / 右心不全 / Interleukin-6 / 炎症 / 肺高血圧症 / 血管内皮機能障害

Outline of Final Research Achievements

In this study, we used the severe PAH model (SuHx) to test the hypothesis that the onset of PAH and right heart failure involve inflammatory endothelial dysfunction in the lung and coronary blood vessels. In SuHx rats, Endothelium-dependent vasodilator responses were significantly attenuated in the middle and small arteries in the right coronary artery of SuHx rats. Endothelin receptor antagonist treatment recovered the endothelium-dependent vasodilator responses, improved the inflammatory state of the right ventricle and restored cardiac function. We also created IL-6 knockout (KO) rats using CRISPR/Cas9 genome editing. IL-6KO rats showed significant resistance to PAH. These results suggests that endothelial dysfunction of coronary arteries is involved in the onset of right heart failure, and that inhibition of inflammatory signals may be a promising new treatment for refractory PAH.

Academic Significance and Societal Importance of the Research Achievements

本研究では肺高血圧症における肺血管リモデリングおよび右冠動脈の異常収縮には炎症を背景とする血管内皮機能障害が関与するかについて、肺高血圧症における炎症性シグナルの分子機序から明らかにすることを目的とし、既存の治療薬に適応しない重症疾患患者に対する新たな治療法の確立を目指すものであった。本研究により、IL-6阻害がこれまでの既存の薬剤に適応しない重症肺高血圧患者に対して右心不全の予防や予後改善にまで発展する可能性が期待された。

Research Products

• [Int'l Joint Research] University of Otago(ニュージーランド)
• [Journal Article] Ghrelin Preserves Ischemia-Induced Vasodilation of Male Rat Coronary Vessels Following β-Adrenergic Receptor Blockade (2018)
  • Author(s): Pearson James T、Collie Nicola、Lamberts Regis R、Inagaki Tadakatsu、Yoshimoto Misa、Umetani Keiji、Davis Philip、Wilkins Gerard、Jones Pete P、Shirai Mikiyasu、Schwenke Daryl O
  • Journal Title: Endocrinology Volume: 159 Issue: 4 Pages: 1763-1773
  • DOI: 10.1210/en.2017-03070
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice. (2018)
  • Author(s): Takeshita H, Yamamoto K, Nozato S, Takeda M, Fukada SI, Inagaki T, Tsuchimochi H, Shirai M, Nozato Y, Fujimoto T, Imaizumi Y, Yokoyama S, Nagasawa M, Hamano G, Hongyo K, Kawai T, Hanasaki-Yamamoto H, Takeda S, Takahashi T, Akasaka H, Itoh N, Takami Y, Takeya Y, Sugimoto K, Nakagami H, Rakugi H.
  • Journal Title: J Cachexia Sarcopenia Muscle. Volume: 9 Issue: 5 Pages: 975-986
  • DOI: 10.1002/jcsm.12334
  • Peer Reviewed / Open Access
• [Journal Article] 2.Modified forelimb grip strength test detects aging-associated physiological decline in skeletal muscle function in male mice. (2017)
  • Author(s): Takeshita H, Yamamoto K, Nozato S, Inagaki T, Tsuchimochi H, Shirai M, Yamamoto R, Imaizumi Y, Hongyo K, Yokoyama S, Takeda M, Oguro R, Takami Y, Itoh N, Takeya Y, Sugimoto K, Fukada SI, Rakugi H.
  • Journal Title: Scientific reports Volume: 7 Issue: 1 Pages: 42323-42323
  • DOI: 10.1038/srep42323
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of the microvascular morphology and hemodynamics of breast cancer in mice using SPring-8 synchrotron radiation microangiography. (2017)
  • Author(s): Torii M, Fukui T, Inoue M, Kanao S, Umetani K, Shirai M, Inagaki T, Tsuchimochi H, Pearson JT, Toi M.
  • Journal Title: J Synchrotron Radiat Volume: 24 Issue: 5 Pages: 1039-1047
  • DOI: 10.1107/s1600577517008372
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model. (2017)
  • Author(s): Pearson JT, Yoshimoto M, Chen YC, Sultani R, Edgley AJ, Nakaoka H, Nishida M, Umetani K, Waddingham MT, Jin HL, Zhang Y, Kelly DJ, Schwenke DO, Inagaki T, Tsuchimochi H, Komuro I, Yamashita S, Shirai M.
  • Journal Title: Sci Rep Volume: Dec 22;7(1) Issue: 1 Pages: 18108-18108
  • DOI: 10.1038/s41598-017-18485-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Critical Roles of Interleukin－6／Interleukin－21－Signaling Axis in the Pathogenesis of Pulmonary Arterial Hypertension (2019)
  • Author(s): Inagaki T, Ogo T, Nakaoka Y
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Macitentan reverses impaired coronary vasodilator function in severe pulmonary hypertensive rats (2018)
  • Author(s): Inagaki T,Nakaoka Y
  • Organizer: the23rd Annual Scientific Meeting of International Society of Cardiovascular Pharmacotherapy
  • Int'l Joint Research
• [Presentation] 炎症性サイトカインの肺高血圧症病態における役割 (2018)
  • Author(s): 中岡 良和、稲垣 薫克
  • Organizer: 第3回日本肺高血圧・肺循環学会学術集会
• [Presentation] 肺高血圧症での冠動脈内皮機能障害はマシテンタンで改善される (2018)
  • Author(s): 稲垣 薫克、森 啓悦、中岡 良和
  • Organizer: 第3回日本肺高血圧・肺循環学会学術集会
• [Presentation] プリスタンを用いた新しい膠原病性肺高血圧症モデル作製の試み (2018)
  • Author(s): 森 啓悦、稲垣 薫克、石橋 知彦、岡澤 慎、正木 豪、中岡 良和
  • Organizer: 第3回日本肺高血圧・肺循環学会学術集会
• [Presentation] Cre-mediated recombination in hematopoietic lineage cells of smooth muscle cell-specific targeted Cre mice (2018)
  • Author(s): Ishibashi T, Inagaki T, Mori H, Masaki T, Asano R, Okazawa M, Nakaoka Y.
  • Organizer: The16 Korea－Japan Joint Symposium on Vasucular Biology
  • Int'l Joint Research
• [Presentation] TrkB might have a role for right ventricular homeostasis under chronic hypoxia-induced pulmonary hypertension (2018)
  • Author(s): Okazawa M, Inagaki T, Ishibashi T, Masaki T, Mori H, Asano R, Nakaoka Y
  • Organizer: 第2回日本循環器学会基礎研究フォーラム
• [Presentation] Cre expression in hematopoietic cells of smooth muscle cell-targeted Cre recombination mice (2018)
  • Author(s): Ishibashi T, Inagaki T, Mori H, Masaki T, Asano R, Okazawa M, Nakaoka Y
  • Organizer: 第2回日本循環器学会基礎研究フォーラム
• [Presentation] Pristane might be useful for creating a novel model of CTD-PAH in mice (2018)
  • Author(s): Mori H, Inagaki T, Ishibashi T, Okazawa M, Masaki T, Asano R, Nakaoka Y
  • Organizer: 第2回日本循環器学会基礎研究フォーラム
• [Presentation] A novel mouse model of PAH reflecting inflammation and fibrosis. (2018)
  • Author(s): 森 啓悦、稲垣 薫克、石橋 知彦、岡澤 慎、正木 豪、浅野 遼太郎、熊ノ郷 淳、中岡 良和
  • Organizer: 第23回日本血管病理研究会
• [Presentation] Macitentan reverses impaired right coronary vasodilative function in SuHx rat (2018)
  • Author(s): Tadakatsu Inagaki, Hirotsugu Tsuchimochi, James Pearson, Hiroyoshi Mori, Daryl Schwenke, Keiji Umetani, Mikiyasu Shirai, Yoshikazu Nakaoka.
  • Organizer: The 1st JCS Council Forum on Basic CardioVascular Research
• [Presentation] Macitentan reverses impaired right coronary vasodilative function in SuHx rat model of severe pulmonary arterial hypertension. (2018)
  • Author(s): Tadakatsu Inagaki, Hirotsugu Tsuchimochi, James Pearson, Hiroyoshi Mori, Daryl Schwenke, Keiji Umetani, Mikiyasu Shirai, Yoshikazu Nakaoka.
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] Macitentan treatment ameliorate impaired right coronary vasodilative functio n in SuHx rat model of severe pulmonary arterial hypertension (2018)
  • Author(s): Tadakatsu Inagaki, Hirotsugu Tsuchimochi, James Pearson, Hiroyoshi Mori, Daryl Schwenke, Keiji Umetani, Mikiyasu Shirai, Yoshikazu Nakaoka.
  • Organizer: 第95回日本生理学会大会
• [Presentation] 肺高血圧による右心不全には右冠動脈血管機能低下が関与する (2017)
  • Author(s): 垣 薫克、土持 裕胤、Pearson James、梅谷 啓二、白井 幹康、中岡 良和
  • Organizer: Molecular Cardiovascular Metabolic Conference 2017
• [Presentation] Impaired right coronary vasodilative function in pulmonary hypertensive rat assessed by in vivo synchrotron microangiography. (2017)
  • Author(s): Tadakatsu Inagaki, Hirotsugu Tsuchimochi, James T. Pearson, Daryl O. Schwenke, Keiji Umetani, Mikiyasu Shirai, Yoshikazu Nakaoka.
  • Organizer: The 8th TAKAO International Symposium
  • Int'l Joint Research
• [Remarks] 国立循環器病研究センター・血管生理学部ホームページ
  • URL: http://www.ncvc.go.jp/res/divisions/vascular_physiology/