Investigation on vasopeptidase inhibition and its application to pulmonary hypertension

• Project/Area Number: 23590123
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: EMOTO Noriaki 神戸薬科大学, 薬学部, 教授 (30294218)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: エンドセリン / エンドセリン変換酵素 / ブラジキニン / 肺高血圧症 / 肺線維症 / 遺伝子欠損マウス / ブラジキニンニン / ナトリウム利尿ペプチド

Research Abstract

We have investigated the possibilities that endothelin-converting enzyme (ECE) is involved in the pathogenesis of pulmonary hypertension and pulmonary fibrosis through other vasoactive peptides in addition to endothelin by using genetically modified mice. We have demonstrated that ECE heterozygous mice were resistant to develop hypoxia-induce pulmonary hypertension by upregulating bradykinin system. We also showed that ECE heterozygous mice were resistant to induce bleomycin-induced pulmonary fibrosis by potentiating CGRP pathway. These results suggest that ECE plays an important role to the pathogenesis of pulmonary hypertension and pulmonary fibrosis, and that ECE may be a plausible target for the therapeutic intervention to these disorders.

Research Products

• [Journal Article] Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice : Potential roles of interleukin-6 and endothelin (2014)
  • Author(s): Van Hung T, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata KI
  • Journal Title: Life Sci Volume: (in press)
• [Journal Article] Vascular endothelium derived endothelin-1 is required for normal heart function after chronic pressure overload in mice (2014)
  • Author(s): Heiden S, Vignon-Zellweger N, Masuda S, Yagi K, Nakayama K, Yanagisawa M, Emoto N
  • Journal Title: PLOS ONE Volume: (in press)
• [Journal Article] Inhibition of vascular endothelial growth factor receptor under hypoxia causes severe, human-like pulmonary arterial hypertension in mice:Potential roles of interleukin-6 and endothelin. (2014)
  • Author(s): Van Hung T, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata KI.
  • Journal Title: Life Science Volume: 印刷中
  • DOI: 10.1016/j.lfs.2013.12.215
  • Peer Reviewed
• [Journal Article] Vascular endothelium derived endothelin-1 is required for normal heart function after chronic pressure overload in mice. (2014)
  • Author(s): Heiden S, Vignon-Zellweger N, Masuda S, Yagi K, Nakayama K, Yanagisawa M, Emoto N.
  • Journal Title: PLoS One. Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Chronic hyperaldosteronism in Cryptochrome null mice induces high-salt- and blood pressure-independent kidney damage in mice. (2014)
  • Author(s): Nugrahaningsih DAA, Emoto N, Vignon-Zellweger N, Purnomo E, Yagi K, Nakayama K, Doi M, Okamura H, and Hirata KI
  • Journal Title: Hypertens Res. Volume: 37 Pages: 202-209
  • DOI: 10.1038/hr.2013.143
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Non-invasive and Simple Assessment of Cardiac Output and Pulmonary Vascular Resistance with Whole-body Impedance Cardiography is Useful for Monitoring Patients with Pulmonary Hypertension (2013)
  • Author(s): Taniguchi Y, Emoto N, Miyagawa K, Nakayama K, Kinutani H, Tanaka H, Shinke T, Hirata, K
  • Journal Title: Circ J Volume: (in press)
• [Journal Article] Endothelin-converting enzyme-1 gene ablation attenuates pulmonary fibrosis via CGRP–cAMP/EPAC1 pathway (2013)
  • Author(s): Hartopo AB, Emoto N, Vignon-Zellweger N, Suzuki Y, Yagi K, Nakayama K, Hirata KI
  • Journal Title: Am. J. Respir. Cell Mol. Biol Volume: 48 Pages: 465-476
• [Journal Article] Michael addition-aromatization reaction of dienylimines bearing a leaving group and its application to the preparation of thiol-selective labeling reagents capable of forming strong carbon-sulfur bonds. (2013)
  • Author(s): Miyoshi M, Aoki Y, Uno Y, Araki M, Kamatani T, Fujii D, Fujita Y, Takeda N, Ueda M, Kitagawa H, Emoto N, Mukai T, Tanaka M, Miyata O.
  • Journal Title: J Org Chem. Volume: 78 Pages: 11433-11443
  • DOI: 10.1021/jo402002k
  • Peer Reviewed
• [Journal Article] Glycosaminoglycan overproduction in the aorta increases aortic calcification in murine chronic kidney disease. (2013)
  • Author(s): Purnomo E, Emoto N, Nugrahaningsih DAA, Nakayama K, Yagi K, Heiden S, Nadanaka S, Kitagawa H, Hirata KI.
  • Journal Title: J. Am. Heart Assoc. Volume: 2
  • DOI: 10.1161/jaha.113.000405
  • Peer Reviewed
• [Journal Article] A New Class of Drug for Pulmonary Arterial Hypertension: Can a Rho-kinase Inhibitor Break the Stagnation in Treating It? (2013)
  • Author(s): Miyagawa K, Emoto N.
  • Journal Title: Circ J. Volume: 77 Pages: 2477-2478
  • Peer Reviewed
• [Journal Article] Activation of Wnt5a-Ror2 signaling associated with epithelial-to-mesenchymal transition of tubular epithelial cells during renal fibrosis. (2013)
  • Author(s): Li, X., Yamagata, K., Nishita, M., Endo, M., Arfian, N., Rikitake, Y., Emoto, N., Hirata, K., Tanaka, Y., Minami, Y.
  • Journal Title: Genes Cells Volume: 18 Pages: 608-19
  • DOI: 10.1111/gtc.12064
  • Peer Reviewed
• [Journal Article] Non-invasive and Simple Assessment of Cardiac Output and Pulmonary Vascular Resistance with Whole-body Impedance Cardiography is Useful for Monitoring Patients with Pulmonary Hypertension. (2013)
  • Author(s): Taniguchi Y, Emoto N, Miyagawa K, Nakayama K, Kinutani H, Tanaka H, Shinke T, Hirata, K.
  • Journal Title: Circ J. Volume: 77 Pages: 2483-2489
  • Peer Reviewed
• [Journal Article] Subsequent Shunt Closure after Targeted Medical Therapy can be an Effective Strategy for Secundum Atrial Septal Defect with Severe Pulmonary Arterial Hypertension. (2013)
  • Author(s): Taniguchi Y, Emoto N, Miyagawa K, Nakayama K, Kinutani H, Tanaka H, Shinke T, Okada K, Okita Y, Hirata, K.
  • Journal Title: Heart Vessels. Volume: 29 Pages: 282-285
  • DOI: 10.1007/s00380-013-0351-0
  • Peer Reviewed
• [Journal Article] Endothelin-converting enzyme-1 gene ablation attenuates pulmonary fibrosis via CGRP–cAMP/EPAC1 pathway. (2013)
  • Author(s): Hartopo AB, Emoto N, Vignon-Zellweger N, Suzuki Y, Yagi K, Nakayama K, Hirata K.
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: 48 Pages: 465-476
  • DOI: 10.1165/rcmb.2012-0354oc
  • Peer Reviewed
• [Journal Article] Efficacy of right ventricular free-wall longitudinal speckle-tracking strain for predicting long-term outcome in patients with pulmonary hypertension. (2013)
  • Author(s): Motoji Y, Tanaka H, Fukuda Y, Ryo K, Emoto N, Kawai H, Hirata K.
  • Journal Title: Circ J. Volume: 77 Pages: 756-763
  • Peer Reviewed
• [Journal Article] ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury (2012)
  • Author(s): Arfian N, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Hirata KI
  • Journal Title: Biochem Biophys Res Commun Volume: 425 Pages: 443-449
• [Journal Article] Physiological relevance of hydrolysis of atrial natriuretic peptide by endothelin-converting enzyme-1 (2012)
  • Author(s): Nakayama K, Emoto E, Suzuki Y, Vignon-Zellweger N, Yagi K, Hirata KI
  • Journal Title: Kobe J. Med. Sci Volume: 58
• [Journal Article] Molecular Biology of Endothelin-1 in the Renal and Cardiovascular Systems (2012)
  • Author(s): Vignon-Zellweger N, Heiden S, Miyauchi T, Emoto N
  • Journal Title: Life Sci Volume: 91 Pages: 490-500
• [Journal Article] ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy (2012)
  • Author(s): Adiarto S, Heiden S, Vignon-Zellweger N, Nakayama K, Yagi K, Yanagisawa M, Emoto N
  • Journal Title: Life Sci Volume: 91 Pages: 651-657
• [Journal Article] Differences in hemodynamic parameters and exercise capacity between patients with pulmonary arterial hypertension and chronic heart failure. (2012)
  • Author(s): Nishio R, Tanaka H, Tsuboi Y, Kinutani H, Taniguchi Y, Shigeru M, Toh R, Miura Y, Sakai Y, Emoto N, Kawai H, Hirata K.
  • Journal Title: J Cardiopulm Rehabil Prev. Volume: 32 Pages: 379-385
  • DOI: 10.1097/hcr.0b013e318272bc0b
  • Peer Reviewed
• [Journal Article] Physiological relevance of hydrolysis of atrial natriuretic peptide by endothelin-converting enzyme-1. (2012)
  • Author(s): Nakayama K, Emoto N, Suzuki Y, Vignon-Zellweger N, Yagi K, Hirata K.
  • Journal Title: Kobe J Med Sci. Volume: 58
  • Peer Reviewed
• [Journal Article] ET-1 deletion from endothelial cells protects the kidney during the extension phase of ischemia/reperfusion injury. (2012)
  • Author(s): Arfian N, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Hirata K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 425 Pages: 443-449
  • DOI: 10.1016/j.bbrc.2012.07.121
  • Peer Reviewed
• [Journal Article] Comparison of medium-dose losartan/hydrochlorothiazide and maximal-dose angiotensin II receptor blockers in the treatment of Japanese patients with uncontrolled hypertension: the Kobe-CONNECT Study. (2012)
  • Author(s): Toh R, Ishida T, Nishimura K, Nonaka H, Inoue Y, Kitagawa Y, Suematsu M, Miki T, Emoto N, Hirata K.
  • Journal Title: Hypertension Res Volume: 35 Pages: 1080-1086
  • DOI: 10.1038/hr.2012.110
  • Peer Reviewed
• [Journal Article] Endothelin and endothelin receptors in the renal and cardiovascular systems. (2012)
  • Author(s): Vignon-Zellweger N, Heiden S, Miyauchi T, Emoto N.
  • Journal Title: Life Sci. Volume: in press
  • Peer Reviewed
• [Journal Article] ET-1 from endothelial cells is required for complete angiotensin II-induced cardiac fibrosis and hypertrophy. (2012)
  • Author(s): Adiarto S, Heiden S, Vignon-Zellweger N, Nakayama K, Yagi K, Yanagisawa M, Emoto N.
  • Journal Title: Life Sci. Volume: in press
  • Peer Reviewed
• [Journal Article] Renal function and blood pressure: molecular insights into the biology of endothelin-1. (2011)
  • Author(s): Vignon-Zellweger N, Heiden S, Emoto N.
  • Journal Title: Contrib Nephrol. Volume: 172 Pages: 18-34
  • Peer Reviewed
• [Journal Article] Utility of right ventricular free wall speckle-tracking strain for evaluation of right ventricular performance in patients with pulmonary hypertension. (2011)
  • Author(s): Fukuda Y, Tanaka H, Sugiyama D, Ryo K, Onishi T, Fukuya H, Nogami M, Ohno Y, Emoto N, Kawai H, Hirata K.
  • Journal Title: J Am Soc Echocardiogr. Volume: 24 Pages: 1101-1108
  • Peer Reviewed
• [Journal Article] Correlation of C4ST-1 and ChGn-2 expression with chondroitin sulfate chain elongation in atherosclerosis. (2011)
  • Author(s): Anggraeni VY, Emoto N, Yagi K, Mayasari DS, Nakayama K, Izumikawa T, Kitagawa H, Hirata K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 406 Pages: 36-41
  • Peer Reviewed
• [Presentation] B radykinin Attenuated Hypoxia Induced Pulmonary Arterial Hypertension through Bradykinin 2 Receptor (2014)
  • Author(s): Suzuki Y, Raharjo SB, Nakayama K, Yagi K, Miyagawa K, Satwiko MG, Muliawan HS, Emoto N
  • Organizer: The 7th Asian Pacific Congress of Heart Failure
• [Presentation] Fulton's Index was Considerably Higher in Endothelin-1 Transgenic Mice Compared to Their Littermates in Hypoxic Induced Pulmonary Arterial Hypertension but not Significantly between Gender (2014)
  • Author(s): Satwiko MG, Nakayama K, Yagi K, Miyagawa K, Suzuki Y, Muliawan HS, Hirata KI, Emoto N
  • Organizer: The 7th Asian Pacific Congress of Heart Failure
• [Presentation] Endothelin Receptor Antagonist and Heart Failure (2014)
  • Author(s): Emoto N.
  • Organizer: 7th Asian Pacific Congress of Heart Failure and 23rd Annual Scientific Meeting of Indonesian Heart Association
  • Place of Presentation: インドネシア
  • Invited
• [Presentation] Bradykinin Attenuated Hypoxia Induced Pulmonary Arterial Hypertension through Bradykinin 2 Receptor. (2014)
  • Author(s): Suzuki Y, Raharjo SB, Nakayama K, Yagi K, Miyagawa K, Satwiko MG, Muliawan HS, Emoto N
  • Organizer: The 7th Asian Pacific Congress of Heart Failure.
  • Place of Presentation: インドネシア
• [Presentation] Endothelin converting enzyme inhibition attenuates early albuminuria and late renal failure in streptozotocin induced diabetic mice (2013)
  • Author(s): Nakayama K, Vignon-Zellweger N, Heiden S, Suzuki Y, Okano T, Miyagawa K, Yagi K, Yanagisawa M, Emoto N
  • Organizer: ET-13: The 13th International Conference on Endothelin
• [Presentation] Role of Bradykinin and Endothelin-Converting Enzyme-1 in Pulmonary Hypertension (2013)
  • Author(s): Raharjo SB, Emoto N, Yuniadi Y, Nakayama K, Harimurti GM
  • Organizer: ET-13: The 13th International Conference on Endothelin
• [Presentation] 肺高血圧症の診断および治療戦略の再構築 (2013)
  • Author(s): 江本憲昭
  • Organizer: 第61回日本心臓病学会学術集会
  • Place of Presentation: 熊本
• [Presentation] 96. Analysis of ET-1 system in mild and severe pulmonary arterial hypertension in mice. (2013)
  • Author(s): Hung TV, Emoto N, Vignon-Zellweger N, Nakayama K, Yagi K, Suzuki Y, Hirata KI
  • Organizer: ET-13: The 13th International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Role of Bradykinin and Endothelin-Converting Enzyme-1 in Pulmonary Hypertension. (2013)
  • Author(s): Raharjo SB, Emoto N, Yuniadi Y, Nakayama K, Harimurti GM
  • Organizer: ET-13: The 13th International Conference on Endothelin
  • Place of Presentation: 東京
• [Presentation] Endothelial cell-derived Endothelin-1 Knock-out Preserves Cortex Architecture after Ischemic-reperfusion Episode in Mice (2012)
  • Author(s): Arfian N, Yagi K, Nakayama K, Ali H, Mayasari DS, Purnomo E, Emoto N
  • Organizer: 49th Congress of the European-Renal-Association/European -Dialysis-and-Transplant-Associatio n (ERA-EDTA)
• [Presentation] Deletion of Endothelin-1 from Endothelial Cell In vivo and ETAR Blocking In vitro Attenuate Fibrosis and Myofibroblast Formation (2012)
  • Author(s): Arfian N, Emoto N, Yagi K, Nakayama K, Ali H, Hartopo AB, Nugrahaningsih DA, Yanagisawa M, Hirata KI
  • Organizer: 49th Congress of the European-Renal-Association/European -Dialysis-and-Transplant-Associatio n (ERA-EDTA)
• [Presentation] Potentiating bradykinin pathway by genetic suppression of endothelin-converting enzyme-1 prevented hypoxic induced pulmonary hypertension and right ventricular hypertrophy (2011)
  • Author(s): Suzuki Y, Raharjo SB, Nakayama K, Vignon-Zellweger N, Heiden S, Arfian N, Hartopo AB, Yagi K, Emoto N
  • Organizer: ET-12: The 12th International Conference on Endothelin
• [Presentation] Endothelin converting enzyme-1 genetic inhibition prevents bleomycin-induced pulmonary fibrosis in mice (2011)
  • Author(s): Hartopo AB, Arfian N, Nugrahaningsih DAA, Vignon-Zellweger N, Heiden S, Nakayama N, Yagi Y, Hirata KI, Emoto N
  • Organizer: ET-12: The 12th International Conference on Endothelin
• [Presentation] Role of endothelin-converting enzyme-1 inhibition in pulmonary vein remodeling during development of secondary pulmonary hypertension (2011)
  • Author(s): Hartopo AB, Emoto N, Yagi K, Nakayama K, Anggraeni VY, Ali H, Arfian N, Mayasari DS, Nugrahaningsih DAA, Purnomo E, Hirata KI
  • Organizer: 18th Congress of Asia Pacific Society of Cardiology
• [Presentation] ENDOTHELIN CONVERTING ENZYME-1 GENETIC INHIBITION PREVENTS BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN MICE (2011)
  • Author(s): Anggoro B. Hartopo, Nur Arfian, Dwi A. A. Nugrahaningsih, Nicolas Vignon-Zellweger, Susi Heiden, Kazuhiko Nakayama, Keiko Yagi, Ken-ichi Hirata, Noriaki Emoto
  • Organizer: The 12th International Conference on Endothelin
  • Place of Presentation: Cambridge
• [Presentation] Potentiating Bradykinin Pathway by Genetic Suppression of Endothelin-converting Enzyme-1 Prevented Hypoxic induced Pulmonary Hypertension and Right Ventricular Hypertrophy. (2011)
  • Author(s): Yoko Suzuki, Sunu Budhi Raharjo, Kazuhiko Nakayama, Nicolas Vignon, Susi Heiden, Nur Arfian, Anggoro Budi Hartopo, Keiko Yagi, Noriaki Emoto
  • Organizer: The 12th International Conference on Endothelin
  • Place of Presentation: Cambridge
• [Presentation] 「肺高血圧」エンドセリンのトランスレーショナルリサーチ¬―心不全、肺高血圧から糖尿病性腎症まで―
  • Author(s): 江本憲昭
  • Organizer: 日本循環器学会 第142回東海・第127回北陸合同地方会
  • Place of Presentation: 金沢
  • Invited
• [Presentation] 肺高血圧症におけるエンドセリン変換酵素ー病態への関与と治療標的としての展望ー
  • Author(s): 江本憲昭
  • Organizer: 第17回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 浜松
  • Invited
• [Presentation] エンドセリンのトランスレーショナルリサーチー分子遺伝学的研究から肺高血圧症の治療応用までー
  • Author(s): 江本憲昭
  • Organizer: 第60回日本心臓病学会学術集会
  • Place of Presentation: 金沢
  • Invited
• [Presentation] エンドセリンによる心血管リモデリングー体血管と肺血管の類似点と相違点ー
  • Author(s): 江本憲昭
  • Organizer: 第35回日本高血圧学会総会
  • Place of Presentation: 金沢
  • Invited
• [Presentation] Molecular Dissection of Pathophysiological Roles of the Endothelin System in Pulmonary Arterial Hypertension: Lessons from Genetically Mofdified Mice
  • Author(s): 江本憲昭
  • Organizer: 第76回日本循環器学会総会
  • Place of Presentation: 横浜
  • Invited
• [Remarks]
  • URL: http://www.kobepharma-u.ac.jp/~clinical/publications/index.html