Investigation on vasopeptidase inhibition and its application to pulmonary hypertension

2013 Fiscal Year Final Research Report

• 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
• 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

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] 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] 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 Pages: E12-18
• [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
• [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
  • Year and Date: 20140000
• [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
  • Year and Date: 20140000
• [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
  • Year and Date: 20130000
• [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
  • Year and Date: 20130000
• [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)
  • Year and Date: 20120000
• [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)
  • Year and Date: 20120000
• [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
  • Year and Date: 20110000
• [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
  • Year and Date: 20110000
• [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
  • Year and Date: 20110000
• [Remarks]
  • URL: http://www.kobepharma-u.ac.jp/~clinical/publications/index.html